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Kurzweill Reports in Medical Science I

Posted in Alzheimer's Disease, Bacterial Resistance, Behavioral Genetics, Cardiac and Cardiovascular Surgical Procedures, Clinical & Translational, Clinical Genomics, Curation, Developmental biology, Embryology, Genetics & Pharmaceutical, Genome Biology, Human aging, Infectious Disease & New Antibiotic Targets, Innovations in Neurophysiology & Neuropsychology, Investment in Technological Breakthrough, Medical Imaging Technology, Microbiologial genetics, Microbiology, Molecular Genetics & Pharmaceutical, Myocardial Ischemia, Neurodegenerative Diseases, Neurological Diseases, Neuroscience, PCI, Pharmacotherapy and Cell Activity, tagged , , , , , , on November 21, 2015| Leave a Comment »

Kurzweill Reports in Medical Science I

Curator: Larry H. Bernstein, MD, FCAP

 

 

 

E-coli bacteria found in some China farms and patients cannot be killed with antiobiotic drug of last resort

“One of the most serious global threats to human health in the 21st century” — could spread around the world, requiring “urgent coordinated global action”
November 20, 2015

http://www.kurzweilai.net/e-coli-bacteria-found-in-some-china-farms-and-patients-cannot-be-killed-with-antiobiotic-drug-of-last-resort

Colistin antibiotic overused in farm animals in China apparently caused E-coli bacteria to become completely resistant to treatment; E-coli strain has already spread to Laos and Malaysia (credit: Yi-Yun Liu et al./Lancet Infect Dis)

Widespread E-coli bacteria that cannot be killed with the antiobiotic drug of last resort — colistin — have been found in samples taken from farm pigs, meat products, and a small number of patients in south China, including bacterial strains with epidemic potential, an international team of scientists revealed in a paper published Thursday Nov. 19 in the journal The Lancet Infectious Diseases.

The scientists in China, England, and the U.S. found a new gene, MCR-1, carried in E-coli bacteria strain SHP45. MCR-1 enables bacteria to be highly resistant to colistin and other polymyxins drugs.

“The emergence of the MCR-1 gene in China heralds a disturbing breach of the last group of antibiotics — polymixins — and an end to our last line of defense against infection,” said Professor Timothy Walsh, from the Cardiff University School of Medicine, who collaborated on this research with scientists from South China Agricultural University.

Walsh, an expert in antibiotic resistance, is best known for his discovery in 2011 of the NDM-1 disease-causing antibiotic-resistant superbug in New Delhi’s drinking water supply. “The rapid spread of similar antibiotic-resistant genes such as NDM-1 suggests that all antibiotics will soon be futile in the face of previously treatable gram-negative bacterial infections such as E.coli and salmonella,” he said.

Likely to spread worldwide; already found in Laos and Malaysia

The MCR-1 gene was found on plasmids — mobile DNA that can be easily copied and transferred between different bacteria, suggesting an alarming potential to spread and diversify between different bacterial populations.

Structure of plasmid pHNSHP45 carrying MCR-1 from Escherichia coli strain SHP45 (credit: Yi-Yun Liu et al./Lancet Infect Dis)

“We now have evidence to suggest that MCR-1-positive E.coli has spread beyond China, to Laos and Malaysia, which is deeply concerning,” said Walsh.  “The potential for MCR-1 to become a global issue will depend on the continued use of polymixin antibiotics, such as colistin, on animals, both in and outside China; the ability of MCR-1 to spread through human strains of E.coli; and the movement of people across China’s borders.”

“MCR-1 is likely to spread to the rest of the world at an alarming rate unless we take a globally coordinated approach to combat it. In the absence of new antibiotics against resistant gram-negative pathogens, the effect on human health posed by this new gene cannot be underestimated.”

“Of the top ten largest producers of colistin for veterinary use, one is Indian, one is Danish, and eight are Chinese,” The Lancet Infectious Diseases notes. “Asia (including China) makes up 73·1% of colistin production with 28·7% for export including to Europe.29 In 2015, the European Union and North America imported 480 tonnes and 700 tonnes, respectively, of colistin from China.”

Urgent need for coordinated global action

“Our findings highlight the urgent need for coordinated global action in the fight against extensively resistant and pan-resistant gram-negative bacteria,” the journal paper concludes.

“The implications of this finding are enormous,” an associated editorial comment to the The Lancet Infectious Diseases paper stated. “We must all reiterate these appeals and take them to the highest levels of government or face increasing numbers of patients for whom we will need to say, ‘Sorry, there is nothing I can do to cure your infection.’”

Margaret Chan, MD, Director-General of the World Health Organization, warned in 2011 that “the world is heading towards a post-antibiotic era, in which many common infections will no longer have a cure and, once again, kill unabated.”

“Although in its 2012 World Health Organization Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR) report the WHO concluded that colistin should be listed under those antibiotics of critical importance, it is regrettable that in the 2014 Global Report on Surveillance, the WHO did not to list any colistin-resistant bacteria as part of their ‘selected bacteria of international concern,’” The Lancet Infectious Diseases paper says, reflecting WHO’s inaction in Ebola-stricken African countries, as noted last September by the international medical humanitarian organization Médecins Sans Frontières.

Funding for the E-coli bacteria study was provided by the Ministry of Science and Technology of China and National Natural Science Foundation of China.

Abstract of Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study

Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via
horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae.

The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model.

Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10−1 to 10−3 cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011–14, and 16 (1%) of 1322 samples from inpatients with infection.

The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria.

references:

 

Researchers discover signaling molecule that helps neurons find their way in the developing brain

November 20, 2015

http://www.kurzweilai.net/researchers-discover-signaling-molecule-that-helps-neurons-find-their-way-in-the-developing-brain

This image shows a section of the spinal cord of a mouse embryo. Neurons appear green. Commissural axons (which connect the two sides of the brain) appear as long, u-shaped threads, and the bottom, yellow segment of the structure represents the midline (between brain hemispheres). (credit: Laboratory of Brain Development and Repair/ The Rockefeller University)

Rockefeller University researchers have discovered a molecule secreted by cells in the spinal cord that helps guide axons (neuron extensions) during a critical stage of central nervous system development in the embryo. The finding helps solve the mystery: how do the billions of neurons in the embryo nimbly reposition themselves within the brain and spinal cord, and connect branches to form neural circuits?

Working in mice, the researchers identified an axon guidance factor, NELL2, and explained how it makes commissural axons (which connect the two sides of the brain).

The findings could help scientists understand what goes wrong in a rare disease called horizontal gaze palsy with progressive scoliosis. People affected by the condition often suffer from abnormal spine curvature, and are unable to move their eyes horizontally from side to side. The study was published Thursday Nov. 19 in the journal Science.

Abstract of Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2

Axon pathfinding is orchestrated by numerous guidance cues, including Slits and their Robo receptors, but it remains unclear how information from multiple cues is integrated or filtered. Robo3, a Robo family member, allows commissural axons to reach and cross the spinal cord midline by antagonizing Robo1/2–mediated repulsion from midline-expressed Slits and potentiating deleted in colorectal cancer (DCC)–mediated midline attraction to Netrin-1, but without binding either Slits or Netrins. We identified a secreted Robo3 ligand, neural epidermal growth factor-like-like 2 (NELL2), which repels mouse commissural axons through Robo3 and helps steer them to the midline. These findings identify NELL2 as an axon guidance cue and establish Robo3 as a multifunctional regulator of pathfinding that simultaneously mediates NELL2 repulsion, inhibits Slit repulsion, and facilitates Netrin attraction to achieve a common guidance purpose.

references:

Topics: Cognitive Science/Neuroscience

A sensory illusion that makes yeast cells self-destruct

A possible tactic for cancer therapeutics
November 20, 2015

http://www.kurzweilai.net/a-sensory-illusion-that-makes-yeast-cells-self-destruct

 

Effects of osmotic changes on yeast cell growth. (A) Schematic of the flow chamber used to create osmotic level oscillations for different periods of time. (B) Cell growth for these periods. The graphs show the average number of progeny cells (blue) before and after applying stress for different periods (gray shows orginal “no stress” line). The inset shows representative images of cells for two periods. (credit: Amir Mitchell et al./Science)

UC San Francisco researchers have discovered that even brainless single-celled yeast have “sensory biases” that can be hacked by a carefully engineered illusion — a finding that could be used to develop new approaches to fighting diseases such as cancer.

In the new study, published online Thursday November 19 in Science Express, Wendell Lim, PhD, the study’s senior author*, and his team discovered that yeast cells falsely perceive a pattern of osmotic levels (by applying potassium chloride) that alternate in eight minute intervals as massive, continuously increasing stress. In response, the microbes over-respond and kill themselves. (In their natural environment, salt stress normally gradually increases.)

The results, Lim says, suggest a whole new way of looking at the perceptual abilities of simple cells and this power of illusion could even be used to develop new approaches to fighting cancer and other diseases.

“Our results may also be relevant for cellular signaling in disease, as mutations affecting cellular signaling are common in cancer, autoimmune disease, and diabetes,” the researchers conclude in the paper. “These mutations may rewire the native network, and thus could modify its activation and adaptation dynamics. Such network rewiring in disease may lead to changes that can be most clearly revealed by simulation with oscillatory inputs or other ‘non-natural’ patterns.

“The changes in network response behaviors could be exploited for diagnosis and functional profiling of disease cells, or potentially taken advantage of as an Achilles’ heel to selectively target cells bearing the diseased network.”

https://youtu.be/CuDjZrM8xtA
UC San Francisco (UCSF) | Sensory Illusion Causes Cells to Self-Destruct

* Chair of the Department of Cellular and Molecular Pharmacology at UCSF, director of the UCSF Center for Systems and Synthetic Biology, and a Howard Hughes Medical Institute (HHMI) investigator.

** Normally, sensor molecules in a yeast cell detect changes in salt concentration and instruct the cell to respond by producing a protective chemical. The researchers found that the cells were perfectly capable of adapting when they flipped the salt stress on and off every minute or every 32 minutes. But to their surprise, when they tried an eight-minute oscillation of precisely the same salt level the cells quickly stopped growing and began to die off.

Abstract of Oscillatory stress stimulation uncovers an Achilles’ heel of the yeast MAPK signaling network

Cells must interpret environmental information that often changes over time. We systematically monitored growth of yeast cells under various frequencies of oscillating osmotic stress. Growth was severely inhibited at a particular resonance frequency, at which cells show hyperactivated transcriptional stress responses. This behavior represents a sensory misperception—the cells incorrectly interpret oscillations as a staircase of ever-increasing osmolarity. The misperception results from the capacity of the osmolarity-sensing kinase network to retrigger with sequential osmotic stresses. Although this feature is critical for coping with natural challenges—like continually increasing osmolarity—it results in a tradeoff of fragility to non-natural oscillatory inputs that match the retriggering time. These findings demonstrate the value of non-natural dynamic perturbations in exposing hidden sensitivities of cellular regulatory networks.

references:

Topics: Biotech

Google Glass helps cardiologists complete difficult coronary artery blockage surgery

November 20, 2015

http://www.kurzweilai.net/google-glass-helps-cardiologists-in-challenging-coronary-artery-blockage-surgery

 

Google Glass allowed the surgeons to clearly visualize the distal coronary vessel and verify the direction of the guide wire advancement relative to the course of the occluded vessel segment. (credit: Maksymilian P. Opolski et al./Canadian Journal of Cardiology

Cardiologists from the Institute of Cardiology, Warsaw, Poland have used Google Glass in a challenging surgical procedure, successfully clearing a blockage in the right coronary artery of a 49-year-old male patient and restoring blood flow, reports the Canadian Journal of Cardiology.

Chronic total occlusion, a complete blockage of the coronary artery, sometimes referred to as the “final frontier in interventional cardiology,” represents a major challenge for catheter-based percutaneous coronary intervention (PCI), according to the cardiologists.

That’s because of the difficulty of recanalizing (forming new blood vessels through an obstruction) combined with poor visualization of the occluded coronary arteries.

Coronary computed tomography angiography (CTA) is increasingly used to provide physicians with guidance when performing PCI for this procedure. The 3-D CTA data can be projected on monitors, but this technique is expensive and technically difficult, the cardiologists say.

So a team of physicists from the Interdisciplinary Centre for Mathematical and Computational Modelling of theUniversity of Warsaw developed a way to use Google Glass to clearly visualize the distal coronary vessel and verify the direction of the guide-wire advancement relative to the course of the blocked vessel segment.

Three-dimensional reconstructions displayed on Google Glass revealed the exact trajectory of the distal right coronary artery (credit: Maksymilian P. Opolski et al./Canadian Journal of Cardiology)

The procedure was completed successfully, including implantation of two drug-eluting stents.

“This case demonstrates the novel application of wearable devices for display of CTA data sets in the catheterization laboratory that can be used for better planning and guidance of interventional procedures, and provides proof of concept that wearable devices can improve operator comfort and procedure efficiency in interventional cardiology,” said lead investigatorMaksymilian P. Opolski, MD, PhD, of the Department of Interventional Cardiology and Angiology at the Institute of Cardiology, Warsaw, Poland.

“We believe wearable computers have a great potential to optimize percutaneous revascularization, and thus favorably affect interventional cardiologists in their daily clinical activities,” he said. He also advised that “wearable devices might be potentially equipped with filter lenses that provide protection against X-radiation.

Abstract of First-in-Man Computed Tomography-Guided Percutaneous Revascularization of Coronary Chronic Total Occlusion Using a Wearable Computer: Proof of Concept

We report a case of successful computed tomography-guided percutaneous revascularization of a chronically occluded right coronary artery using a wearable, hands-free computer with a head-mounted display worn by interventional cardiologists in the catheterization laboratory. The projection of 3-dimensional computed tomographic reconstructions onto the screen of virtual reality glass allowed the operators to clearly visualize the distal coronary vessel, and verify the direction of the guide wire advancement relative to the course of the occluded vessel segment. This case provides proof of concept that wearable computers can improve operator comfort and procedure efficiency in interventional cardiology.

references:

Topics: Biomed/Longevity | VR/Augmented Reality/Computer Graphics

Modulating brain’s stress circuity might prevent Alzheimer’s disease

Drug significantly prevented onset of cognitive and cellular effects in mice
November 17, 2015

http://www.kurzweilai.net/modulating-brains-stress-circuity-might-prevent-alzheimers-disease

 

Effect of drug treatment on AD mice in control group (left) or drug (right) on Ab plaque load. (credit: Cheng Zhang et al./Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association)

In a novel animal study design that mimicked human clinical trials, researchers at University of California, San Diego School of Medicine report that long-term treatment using a small-molecule drug that reduces activity of  the brain’s stress circuitry significantly reduces Alzheimer’s disease (AD) neuropathology and prevents onset of cognitive impairment in a mouse model of the neurodegenerative condition.

The findings are described in the current online issue of the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Previous research has shown a link between the brain’s stress signaling pathways and AD. Specifically, the release of a stress-coping hormone called corticotropin-releasing factor (CRF), which is widely found in the brain and acts as a neurotransmitter/neuromodulator, is dysregulated in AD and is associated with impaired cognition and with detrimental changes in tau protein and increased production of amyloid-beta protein fragments that clump together and trigger the neurodegeneration characteristic of AD.

“Our work and that of our colleagues on stress and CRF have been mechanistically implicated in Alzheimer’s disease, but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models,” said the study’s principal investigator and corresponding author Robert Rissman, PhD, assistant professor in the Department of Neurosciences and Biomarker Core Director for the Alzheimer’s Disease Cooperative Study (ADCS).

The researchers determined that modulating the mouse brain’s stress circuitry mitigated generation and accumulation of amyloid plaques widely attributed with causing neuronal damage and death. As a consequence, behavioral indicators of AD were prevented and cellular damage was reduced.  The mice began treatment at 30-days-old — before any pathological or cognitive signs of AD were present — and continued until six months of age.

One particular challenge, Rissman noted, is limiting exposure of the drug to the brain so that it does not impact the body’s ability to respond to stress. “This can be accomplished because one advantage of these types of small molecule drugs is that they readily cross the blood-brain barrier and actually prefer to act in the brain,” Rissman said.

“Rissman’s prior work demonstrated that CRF and its receptors are integrally involved in changes in another AD hallmark, tau phosphorylation,” said William Mobley, MD, PhD, chair of the Department of Neurosciences and interim co-director of the Alzheimer’s Disease Cooperative Study at UC San Diego. “This new study extends those original mechanistic findings to the amyloid pathway and preservation of cellular and synaptic connections.  Work like this is an excellent example of UC San Diego’s bench-to-bedside legacy, whereby we can quickly move our basic science findings into the clinic for testing,” said Mobley.

Rissman said R121919 was well-tolerated by AD mice (no significant adverse effects) and deemed safe, suggesting CRF-antagonism is a viable, disease-modifying therapy for AD. Drugs like R121919 were originally designed to treat generalized anxiety disorder, irritable bowel syndrome and other diseases, but failed to be effective in treating those disorders.

Rissman noted that repurposing R121919 for human use was likely not possible at this point. He and colleagues are collaborating with the Sanford Burnham Prebys Medical Discovery Institute to design new assays to discover the next generation of CRF receptor-1 antagonists for testing in early phase human safety trials.

“More work remains to be done, but this is the kind of basic research that is fundamental to ultimately finding a way to cure — or even prevent —Alzheimer’s disease,” said David Brenner, MD, vice chancellor, UC San Diego Health Sciences and dean of UC San Diego School of Medicine. “These findings by Dr. Rissman and his colleagues at UC San Diego and at collaborating institutions on the Mesa suggest we are on the cusp of creating truly effective therapies.”

Abstract of Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer’s disease

Introduction: Stress and corticotropin-releasing factor (CRF) have been implicated as mechanistically involved in Alzheimer’s disease (AD), but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models.

Methods: To test whether antagonism of the type-1 corticotropin-releasing factor receptor (CRFR1) could be used as a disease-modifying treatment for AD, we used a preclinical prevention paradigm and treated 30-day-old AD transgenic mice with the small-molecule, CRFR1-selective antagonist, R121919, for 5 months, and examined AD pathologic and behavioral end points.

Results: R121919 significantly prevented the onset of cognitive impairment in female mice and reduced cellular and synaptic deficits and beta amyloid and C-terminal fragment-β levels in both genders. We observed no tolerability or toxicity issues in mice treated with R121919.

Discussion: CRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials.

references:

Topics: Cognitive Science/Neuroscience

Allen Institute researchers decode patterns that make our brains human
Conserved gene patterning across human brains provide insights into health and disease
November 17, 2015

http://www.kurzweilai.net/allen-institute-researchers-decode-patterns-that-make-our-brains-human

 

Percentage of known neuron-, astrocyte- and oligodendrocyte-enriched genes in 32 modules, ordered by proportion of neuron-enriched gene membership. (credit: Michael Hawrylycz et al./Nature Neuroscience)

Allen Institute researchers have identified a surprisingly small set of just 32 gene-expression patterns for all 20,000 genes across 132 functionally distinct human brain regions, and these patterns appear to be common to all individuals.

In research published this month in Nature Neuroscience, the researchers used data for six brains from the publicly available Allen Human Brain Atlas. They believe the study is important because it could provide a baseline from which deviations in individuals may be measured and associated with diseases, and could also provide key insights into the core of the genetic code that makes our brains distinctly human.

While many of these patterns were similar in human and mouse, many genes showed different patterns in human. Surprisingly, genes associated with neurons were most conserved (consistent) across species, while those for the supporting glial cells showed larger differences. The most highly stable genes (the genes that were most consistent across all brains) include those associated with diseases and disorders like autism and Alzheimer’s, and these genes include many existing drug targets.

These patterns provide insights into what makes the human brain distinct and raise new opportunities to target therapeutics for treating disease.

The researchers also found that the pattern of gene expression in cerebral cortex is correlated with “functional connectivity” as revealed by neuroimaging data from the Human Connectome Project.

“The human brain is phenomenally complex, so it is quite surprising that a small number of patterns can explain most of the gene variability across the brain,” says Christof Koch, Ph.D., President and Chief Scientific Officer at the Allen Institute for Brain Science. “There could easily have been thousands of patterns, or none at all. This gives us an exciting way to look further at the functional activity that underlies the uniquely human brain.”

Abstract of Canonical genetic signatures of the adult human brain

The structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure and function. We applied a correlation-based metric called differential stability to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing mesoscale genetic organization. The genes with the highest differential stability are highly biologically relevant, with enrichment for brain-related annotations, disease associations, drug targets and literature citations. Using genes with high differential stability, we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely patterned genes displayed marked shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry.

references:

Topics: Biotech

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Important Lead in Alzheimer’s Disease Model

Posted in Alzheimer's Disease, Cell Biology, Signaling & Cell Circuits, Etiology, Neurodegenerative Diseases, Neurological Diseases, Neuroscience, Pharmacotherapy and Cell Activity on November 19, 2015| Leave a Comment »

Important Lead in Alzheimer’s Disease Model

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

UCSD team targeting new stress pathway in Alzheimer’s program

By John Carroll

has long been one of the most frustrating targets in R&D. Despite repeated assurances from rival camps that toxic loads of amyloid beta and tau are likely causes of the diseases, no one is quite sure what is going on and clinical failures are routine. But investigators at UC San Diego School of Medicine say they have been garnering some preclinical clues that would suggest there could be a new pathway to follow in the clinic.

Following the idea that the brain’s stress signaling circuitry may play a role in the development of the disease, the UCSD group centered on a hormone called corticotropin-releasing factor. CRF is a neuropeptide that triggers the behavioral and biologic responses to stress, which UC says has been associated with worsening cognition as well as the alteration of tau and the creation of a-beta.

The team found a way to block the CRF receptor in mouse models for the disease with an anti-anxiety and IBS drug called R121919. Cellular damage was reduced, the scientists say, while the behavioral changes associated with the disease were also avoided in the mice.

“The novelty of this study is two-fold: We used a preclinical prevention paradigm of a CRF-antagonist (a drug that blocks the CRF receptor in brain cells) called R121919 in a well-established AD model–and we did so in a way that draws upon our experience in human trials,” said Robert Rissman, an assistant professor in the Department of Neurosciences and Biomarker Core Director for the Alzheimer’s Disease Cooperative Study, in a release. “We found that R121919 antagonism of CRF-receptor-1 prevented onset of cognitive impairment and synaptic/dendritic loss in AD mice.”

The group followed up by saying that R121919 appeared to be a safe way to hit the stress pathway, but that it was unlikely that they could repurpose the drug specifically for Alzheimer’s. Now the team plans to search for new drugs that can do the same thing, with an eye to getting into the clinic.

“Rissman’s prior work demonstrated that CRF and its receptors are integrally involved in changes in another AD hallmark, tau phosphorylation,” said Dr. William Mobley, chair of the Department of Neurosciences and interim co-director of the Alzheimer’s Disease Cooperative Study at UC San Diego, in the release. “This new study extends those original mechanistic findings to the amyloid pathway and preservation of cellular and synaptic connections. Work like this is an excellent example of UC San Diego’s bench-to-bedside legacy, whereby we can quickly move our basic science findings into the clinic for testing.”

 

Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer’s disease

Cheng Zhang, Ching-Chang Kuo, Setareh H. Moghadam, Louise Monte, Shannon N. Campbell, Kenner C. Rice, Paul E. Sawchenko, Eliezer Masliah, Robert A. Rissman
DOI: http://dx.doi.org/10.1016/j.jalz.2015.09.007http://www.alzheimersanddementia.com/article/S1552-5260(15)02913-1/abstract
Introduction   Stress and corticotropin-releasing factor (CRF) have been implicated as mechanistically involved in Alzheimer’s disease (AD), but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models.

Methods   To test whether antagonism of the type-1 corticotropin-releasing factor receptor (CRFR1) could be used as a disease-modifying treatment for AD, we used a preclinical prevention paradigm and treated 30-day-old AD transgenic mice with the small-molecule, CRFR1-selective antagonist, R121919, for 5 months, and examined AD pathologic and behavioral end points.

Results   R121919 significantly prevented the onset of cognitive impairment in female mice and reduced cellular and synaptic deficits and beta amyloid and C-terminal fragment-β levels in both genders. We observed no tolerability or toxicity issues in mice treated with R121919.

Discussion   CRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials.

 

Preclinical study points to GPR3 as a potential target for Alzheimer’s

October 21, 2015 | By
http://www.fiercebiotechresearch.com/story/preclinical-study-points-gpr3-potential-target-alzheimers/2015-10-21

Scientists and clinicians have tackled Alzheimer’s disease (AD) progression from multiple angles. But two approaches have become the most accepted: halt the accumulation of toxic protein aggregates called tau tangles, or prevent beta amyloid plaques from clustering in the brain, both of which may be responsible for the deterioration of the central nervous system, leading to dementia.

Researchers at the Flanders Interuniversity Institute for Biotechnology are opting for the latter approach, saying that the loss of a protein called G protein-coupled receptor 3 (GPR3) may lower the amyloid plaque aggregation, resulting in improved cognitive function.

 

The role of G protein-coupled receptors in the pathology of Alzheimer’s disease
Amantha Thathiah and Bart De Strooper
Nature Reviews Feb 2011; 12: 73-87

Abstract | G protein-coupled receptors (GPCRs) are involved in numerous key neurotransmitter systems in the brain that are disrupted in Alzheimer’s disease (AD). GPCRs also directly influence the amyloid cascade through modulation of the α-, β- and γ-secretases, proteolysis of the amyloid precursor protein (APP), and regulation of amyloid-β degradation. Additionally, amyloid-β has been shown to perturb GPCR function. Emerging insights into the mechanistic link between GPCRs and AD highlight the potential of this class of receptors as a therapeutic target for AD.

 

Figure 1 | Modulation of APP processing by GPcrs. Cleavage of amyloid precursor protein (APP) by α-secretase generates the soluble amino-terminal ectodomain of APP (sAPPα) and the carboxy-terminal fragment C83. Subsequent cleavage of C83 by the γ-secretase complex yields the APP intracellular domain (AICD) and a short fragment termed p3. Several G protein-coupled receptors (GPCRs), including muscarinic, metabotropic and serotonergic receptors modulate α-secretase-mediated proteolysis. Alternatively, cleavage of APP by β-secretase generates sAPPβ and the C-terminal fragment C99. Subsequent cleavage of C99 by the γ-secretase complex yields the AICD and the amyloid-β peptide. Of the GPCRs that regulate this processing, the δ-opioid receptor (DOR) and the adensoine A2A receptor (A2AR) have been shown to modulate β-secretase-mediated cleavage of APP, whereas the β2 adrenergic receptor (β2-AR), G protein-coupled receptor 3 (GPR3), and CXC-chemokine receptor 2 (CXCR2) have been shown to modulate γ-secretasemediated cleavage of C99 or C83. Aβ, amyloid-β; ADAM, a disintegrin and metalloproteinase; BACE1, β-site APP-converting enzyme 1; CRHR1, corticotrophinreleasing hormone (CRH) receptor type I; 5-HT, 5-hydroxytryptamine (serotonin); mAChR, muscarinic acetylcholine receptor; mGluR, metabotropic glutamate receptor; PAC1R, pituitary adenylate cyclase 1 receptor.

 

Box 1 | The cholinergic and amyloid cascade hypotheses
The amyloid cascade hypothesis The amyloid cascade hypothesis postulates that gradual changes in the metabolism and aggregation of amyloid-β initiates a cascade of neuronal and inflammatory injury that culminates in extensive neuronal dysfunction and cell death associated with neurotransmitter deficits and dementia145,146. The cholinergic hypothesis The cholinergic hypothesis posits that a dysfunction in acetylcholine (ACh)-containing neurons substantially contributes to the cognitive decline observed in Alzheimer’s disease (AD)147. This is based on the observation that cholinergic transmission has a fundamental role in cognition and is disrupted in patients with AD148,149. convergence of the amyloid cascade and cholinergic hypotheses ACh is a key neurotransmitter involved in learning and memory150 that binds to distinct receptor subtypes in the brain: nicotinic ACh receptors (nAChRs) and muscarinic ACh receptors (mAChRs). Nicotinic neurotransmission is implicated in the pathogenesis of AD (TABle 1). Additional evidence suggests that the major mAChR subtypes involved in AD are the postsynaptic M1 mAChRs, which mediate the effects of ACh, and the presynaptic M2 mAChRs, which inhibit ACh release151, 152. Amyloid-β deposition may contribute to the cholinergic dysfunction in AD by decreasing the release of presynaptic ACh and impairing the coupling of postsynaptic M1 mAChRs with G proteins. This leads to decreased signal transduction, impairments in cognition, a reduction in the levels of amyloid precursor protein (APP), the generation of more neurotoxic amyloid-β and a further decrease in ACh release111. Genetic ablation of the M1 mAChR in a transgenic mouse model of AD decreases the production of the soluble amino-terminal ectodomain of APP (sAPPα), increases amyloid-β generation and exacerbates the amyloid plaque pathology28, supporting the development of M1-selective agonists. In addition, M1 mAChR activation reduces tau phosphorylation27,153 and alleviates hippocampus-dependent memory impairments27, making M1 mAChRs a compelling therapeutic target for AD. Furthermore, receptor subtype specificity will be of key importance as M2 and M4 mAChRs seem to inhibit sAPPα release and potentially aggravate amyloid-β generation28,30, and activation of nAChRs exacerbates the tau pathology154.

 

Figure 2 | GPcr signalling and the α-secretase pathway. G protein-coupled receptors (GPCRs) exert their multiple functions through a complex network of intracellular signalling pathways. Ligand-bound GPCRs activate heterotrimeric G proteins, inducing the exchange of GDP for GTP and the formation of a GTP-bound Gα subunit and the release of a Gβγ dimer. The G protein subunits then activate specific secondary effector molecules, such as adenylyl cyclase (AC), phospholipase C (PLC) and phospholipase A2 (PLA2), leading to the generation of secondary messengers and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), Janus kinase (JAK) and phophoinositide 3-kinase (PI3K), and modulation of the α-secretase pathway. In the case of the M1 muscarinic acetylcholine receptor (M1 mAChR), the group I metabotropic glutamate receptors (mGluRs) and the 5-hydroxytryptamine receptors 5-HT2A/2CR and 5-HT4R, agonist stimulation leads to an increase in soluble amyloid precursor protein (sAPP) release, a decrease in amyloid-β (Aβ) generation, a decrease in tau phosphorylation and/or an alleviation of the cognitive deficits in a mouse model of Alzheimer’s disease (AD). Conversely, agonist stimulation of the Group II mGluRs leads to an increase in amyloid-β42 generation, tau phosphorylation and an exacerbation of the cognitive deficits in an AD mouse model. In the case of the 5-HT6 receptor (5-HT6R), antagonism of the receptor leads to an improvement in cognition. Solid arrows represent direct signalling pathways and dashed arrows represent signalling via intermediates that are not shown. ACh, acetylcholine; ADAM, a disintegrin and metalloproteinase; cAMP, cyclic AMP; GSK3β, glycogen synthase kinase 3β; NMDAR, NMDA receptor; PKC, protein kinase C; sAPPα, soluble amino-terminal ectodomain of APP; STAT, signal transducer and activator of transcription.

 

Pituitary adenylate cyclase 1 receptor. The pituitary adenylate cyclase 1 receptor (PAC1R) is a GPCR that is stimulated by the neuropeptide pituitary adenylate cyclase­activating polypeptide (PACAP). The receptor is primarily localized to the hypothalamus but is also expressed in the cerebral cortex and hippocampus72, areas of the human brain affected by AD. The major form of PACAP, composed of 38 amino acids (PACAP38), has been show to improve memory in rats73. Together with a C­terminal truncated form, PACAP27, it stimulates an increase in sAPPα release74. This effect is blocked by a broad­spectrum metalloprotease inhibitor and by an ADAM10­specific inhibitor, GI254023X74. Thus, stimulation of PAC1R enhances α­secretase activity. Although the molecular mechanism of this effect has not been elucidated, neuropeptide hormones such as PACAP27 and PACAP38 display a high flux rate across the blood–brain barrier (bbb)75, which should permit the in vivo examination of the effect of PACAP in a transgenic mouse model of AD.
Regulation of b-secretase The β­secretase bACE1 (β­site APP­converting enzyme 1), is a type I transmembrane aspartyl protease that is active at low pH and is predominantly localized in acidic intracellular compartments, such as endosomes and the trans­Golgi network. Cleavage of APP by bACE1 generates a soluble n­terminal ectodomain of APP (sAPPβ) and the n terminus of amyloid­β. Subsequent cleavage of the membrane­bound C­terminal fragment C99 by the γ­secretase liberates the amyloid­β peptide species (FIG. 1). bACE1 is abundantly expressed in neurons in the brain. Bace1–/– mice are viable and fertile, facilitating the study of the role of this enzyme in AD. bACE1 deficiency in an AD mouse model abrogates amyloid­β generation, amyloid pathology, electrophysiological dysfunction and cognitive deficits, implying that therapeutic inhibition of bACE1 would decrease generation of all amyloid­β species. However, Bace1–/– mice display phenotypic abnormalities that are related to the processing of additional proteins by bACE1, suggesting that therapeutic inhibition of bACE1 could have adverse side effects (reviewed in ReFS 76,77). nevertheless, bACE1 is arguably the primary therapeutic target to deter amyloid­β generation. Detailed structural analysis of bACE1 has led to the discovery of many transition state­based inhibitors with activity in the low nanomolar range, although the in vivo efficacy of these compounds is limited because most of them do not penetrate the bbb or are actively exported from the brain by P­glycoprotein. Recent evidence suggests that GPCRs such as the δ­opioid receptor (DOR)78 could provide a therapeutic opportunity to modulate bACE1 and amyloid­β generation .
δ‑ and μ‑opioid receptors. The opioid receptors, which play important parts in learning and memory, are deregulated in specific regions of the AD brain79. There is evidence to suggest that the DOR, together with the β2 adrenergic receptor (β2­AR), promotes the γ­secretasemediated cleavage of the APP C­terminal fragment after its generation by β­secretase80. A more recent study by the same group suggested that activation of the DOR promotes the translocalization of a complex consisting of the DOR, β­secretase and γ­secretase from the cell surface to the late endosomes and lysosomes (LEL), which results in enhanced β­ and γ­secretase proteolysis of APP78. In a mouse model of AD, administration of natrindole, a selective DOR antagonist, improved spatial learning and reference memory, and reduced the amyloid plaque burden78. Similarly, in vivo knock down of the DOR reduced amyloid­β40 accumulation in the hippoc ampus of an AD mouse model. However, there was no effect on the more hydrophobic (and therefore more toxic) amyloid­β42 (ReF. 78). by contrast, administration of a μ­opioid receptor (MOR) antagonist had no effect on amyloid­β generation or amyloid plaque formation and was unable to reverse the learning and memory deficiency of the AD mouse model78, although another group reported improved spatial memory retention in this transgenic AD mouse model81. DOR binding is decreased in the amygdala and ventral putamen, and MOR binding is decreased in the hippocampus and subiculum79 of post­mortem brain samples from patients with AD. Elevated hippocampal levels of enkephalin, the ligand for these receptors, have been detected in AD transgenic mice and in the human AD brain81,82. Excessive stimulation by enkephalin may uncouple the opioid receptors from G proteins, resulting in receptor internalization83,84 and reduced receptor binding in patients with AD79,85. These adaptive changes in opioid receptor expression in response to increased enkephalin levels might limit the efficacy of opioid receptor antagonists in AD and could explain the variable effects of different DOR antagonists on amyloid­β generation in AD transgenic mouse models.
Regulation of g-secretase The γ-­secretase complex is composed of four integral membrane proteins: the catalytic component presenilin 1 (PS1) or PS2 and the essential cofactors nicastrin, anterior pharynx defective 1 (APH1) and presenilin enhancer 2 (PEn2)86. Proteolysis of the α­ cleavage product C83 by the γ­secretase complex generates a short p3 fragment, which precludes formation of amyloid­β. by contrast, proteolysis of the β­secretase product C99 by the γ­secretase complex generates the amyloid­β peptide, which ranges in length from 35 to 43 residues (FIG. 1). The majority of amyloid­β produced is 40 amino acids in length (amyloid­β40), whereas a small proportion (~10%) is the 42­residue variant (amyloid­β42). Several γ­secretase inhibitors have been developed but they have limited clinical efficacy owing to the severe side effects associated with inhibition of the notch receptor, which is a substrate for γ­secretase proteolysis. Therefore, determination of the cellular mechanisms that specifically regulate amyloid­β generation by γ­secretase is of crucial importance for understanding the factors that cause AD and could highlight new therapeutic targets.

 

b 2‑adrenergic receptor. Stimulation of β2­AR increases amyloid­β generation in vitro, independently of an elevation in cAMP levels80. In an AD transgenic mouse model, treatment with a β2­AR agonist or antagonist respectively increased and decreased the amyloid plaque burden80. It has been suggested that the β2­AR constitutively associates with PS1 at the plasma membrane and undergoes clathrin­mediated endocytosis together with the γ­secretase complex following agonist stimulation80. This proposed localization of the γ­secretase in LEL compartments, which is supported by other studies87,88, could promote cleavage of C99 and thereby the generation of amyloid­β80. As a therapeutic application, it will be important to determine whether β2­AR activation also modulates cleavage of the notch receptor, given the adverse side effects of targeting γ­secretase discussed above. Importantly, the β2­AR is expressed in the hippocampus and the cortex in humans89, and polymorphisms in the gene encoding the β2­AR are associated with an increased risk of developing sporadic lateonset AD90, providing support for the potential clinical relevance of the in vitro and AD mouse model findings.
G protein‑coupled receptor 3. G protein­coupled receptor 3 (GPR3) is an orphan GPCR with a putative ligand91 that has not been validated92,93. The receptor was identified as a modulator of amyloid­β generation in a high­throughput functional genomics screen designed to identify potential therapeutic targets for AD92. GPR3 is strongly expressed in neurons in the hippocampus, amygdala, cortex, entorhinal cortex and thalamus in the normal human brain94,95, and its expression is increased in a subset of patients with sporadic AD92. Several lines of evidence support the involvement of GPR3 in the generation of amyloid­β. In vitro models of AD suggest that this effect is independent of its ability to stimulate the production of cAMP92. In an AD transgenic mouse model96, hippocampal overexpression of GPR3 enhanced amyloid­β40 and amyloid­β42 generation in the absence of an effect on γ­secretase expression92. Genetic ablation of Gpr3 in these mice dramatically reduced amyloid­β40 and amyloid­β42 levels92, demonstrating that endogenous GPR3 is involved in amyloid­β generation. Further in vitro studies suggested that GPR3 promotes increased association of the individual γ­secretase complex components within detergent­resistant membrane domains and stabilizes the mature γ­secretase complex92. Thus, similar to the β2­AR, the effect of GPR3 signalling on amyloid­β generation is not mediated through an elevation in cAMP levels. Rather, both GPCRs modulate the trafficking and/or localization of the γ­secretase complex to membrane domains where it can more efficiently process the β­secretase product C99. Importantly, the in vitro effect of GPR3 expression on amyloid­β generation occurs in the absence of an effect on notch processing, suggesting that GPR3 can selectively target specific γ­secretase pathways.
CXC‑chemokine receptor 2. The CXC­chemokine receptor type 2 (CXCR2) is abundantly expressed in neurons and is strongly upregulated in a subpopulation of neuritic plaques in the post­mortem human AD brain97,98. In an AD transgenic mouse model, treatment with the CXCR2 antagonist Sb­225002 reduces amyloid­β40 levels99 and is accompanied by a reduction in PS1–C­terminal fragment (CTF) levels, resulting in a probable decrease in the proteolytically active mature γ­secretase complex99. Crossing the Cxcr2­deficient mouse with an AD transgenic mouse also results in a decrease in amyloid­β40 and amyloid­β42 generation, and γ­secretase complex expression100. In vitro evidence suggests that antagonism of CXCR2 reduces expression levels of other γ­secretase complex components, inhibiting generation of both the AICD and the notch intracellular domain. Whether CXCR2 is involved in enhanced turnover, degradation or stabilization of the PS1–CTF has not been determined. However, inhibition of Jun n­terminal kinase (JnK) activity, which is involved in signalling downstream of CXCR2, correlates with reduced phosphorylation and stability of the PS1–CTF101,102. Given that antagonism of CXCR2 leads to general changes in γ­secretase expression and activity, it will be challenging to therapeutically target CXCR2.
GPCRs and amyloid-b toxicity One of the most puzzling aspects of the amyloid cascade hypothesis is why amyloid­β exerts a neurotoxic effect on cells. There is no clear correlation between exposure of the brain to amyloid­β plaques and neurodegeneration and, in cell culture models, the toxicity associated with amyloid­β is variable and poorly understood. Small oligomeric structures of amyloid­β, known as amyloidβ­derived diffusible ligands (ADDLs)103, cause synaptotoxicity, interfering with glutamate signalling at several levels, including direct and indirect effects on Ca2+ levels, endocytosis, and possibly membrane damage and clustering of various membrane proteins. A further complication is that a component of the toxicity associated with amyloid­β might be the consequence of a general mechanism such as interaction with the plasma membrane, which could affect multiple GPCRs. Moreover, several GPCRs are involved in neuro inflammation, with beneficial or detrimental effects on amyloid­β­mediated toxicity depending on the model under investigation. Thus, it remains unclear how the involvement of GPCRs in amyloid­-β ­mediated toxicity can be clinically exploited. Studies on the angiotensin type 2 receptor (AT2R), the adenosine A2A receptor (A2AR) and CC­chemokine receptor 2 (CCR2) provide insight into this complicated matter.

 

Figure 3 | Amyloid-β toxicity and deregulation of AT2r and M1 mAchr signalling . Oxidative stress and amyloid-β (Aβ) accumulation leads to an increase in reactive oxygen species (ROS) generation and dimerization of angiotensin type 2 receptors (AT2R). An increase in levels of the protein-crosslinking enzyme transglutaminase, as occurs in Alzheimer’s disease, and further Aβ deposition trigger crosslinking and subsequent oligomerization of AT2R dimers. The AT2R oligomers sequester Gαq/11 and thereby inhibit Gαq/11 from coupling to M1 muscarinic acetylcholine receptors (M1 mAChRs). Sequestration of Gαq/11 results in tau phosphorylation, neuronal degeneration and Alzheimer’s disease progression. PKC, protein kinase C. Figure is reproduced, with permission, from REF. 111 © (2009) American Association for the Advancement of Science.

…….

GPCRs and amyloid-b degradation Promoting amyloid­β clearance from the brain is an alternative therapeutic strategy to inhibition of amyloid­β generation. Such an approach is the basis for the passive and active immunotherapy with amyloid­βspecific antibodies. However, stimulation of GPCRs, in particular the somatostatin receptor, could represent an interesting alternative approach to promoting amyloid­β clearance, as these GPCRs induce expression of amyloidβ­degrading enzymes, such as neprilysin, in the brain. A combination of memory enhancement, neuroprotection and anti­amyloid­β activity makes this an attractive therapeutic approach for AD.
Somatostatin receptors. Somatostatin (also known as somatotropin release­ inhibiting factor, SRIF) is a regulatory peptide with two bioactive forms, SRIF14 and SRIF28, which are widely expressed throughout the CnS and function in neurotransmission, protein secretion and cell proliferation133,134. Expression of the two most abundant SRIF receptors in the brain, somatostatin receptor type 2 (SSTR2) and SSTR4, is reduced in the cortex of human patients with AD135. Interestingly, intracerebroventricular injection of amyloid­β25–35 results in a selective decrease in SSTR2 mRnA and protein levels in the temporal cortex of rats, whereas cognitive deficits correlate with reduced SRIF concentrations in the CSF136 or middle front gyrus (brodmann area 9)137. SRIF levels are also reduced in the CSF136, cortex135 and hippocampus138 of patients with AD. Compelling evidence suggests that SRIF is a modulator of neprilysin activity in the brain139. neprilysin, one of the main amyloid­β­degrading enzymes, regulates the steady state levels of amyloid­β40 and amyloid­β42 in vivo140. SRIF has been shown to significantly elevate neprilysin levels in primary murine cortical neuronal cultures, which accompanies a reduction in amyloid­β42 levels139. Conversely, neprilysin activity and localization are altered in the hippocampus of SRIF­deficient mice, with a corresponding increase in amyloid­β42 levels139. There are conflicting results from AD transgenic mouse models, which show either an increase141 or a decrease in SRIF levels142. Further work is necessary to clarify the cause of the changes in SRIF levels in these AD models.

Figure 4 | Adenosine A2A receptor and amyloid-β-mediated toxicity. a | Amyloid-β (Aβ) deposition has been shown to activate the p38 mitogen-activated protein kinase (MAPK) signalling pathway, which leads to Aβ-induced neurotoxicity. Pharmacological blockade of the adenosine A2A receptor (A2AR) with the compound SCH 58261 reduces Aβ-induced p38 MAPK phosphorylation, synaptotoxicity and cognitive impairment. b | Similarly, caffeine, an A2AR antagonist, is also protective against Aβ-mediated toxicity and may regulate the expression levels of the β-secretase, via the cRaf-1/nuclear factor-κB pathway and presenilin 1, which leads to a decrease in Aβ40 and Aβ42 deposition and is protective against cognitive impairment in an Alzheimer’s disease mouse model. Solid arrows represent direct signalling pathways and dashed arrows represent signalling via intermediates that are not shown. JNK, Jun N-terminal kinase.

 

Box 2 | GPCRs, diabetes and Alzheimer’s disease Glucagon-like peptide 1 receptor Type 2 diabetes (T2D) has been identified as a risk factor for Alzheimer’s disease (AD)155, and insulin signalling has a role in learning and memory156-158, which potentially links insulin resistance to AD dementia. Indeed, deregulated insulin signalling has been observed in brains of patients with AD and may contribute to the development of AD159. The combination of insulin with other antidiabetic medications is also associated with lower amyloid plaque density and a diminution of the cognitive decline associated with AD160,161. Strategies have therefore been developed to normalize insulin signalling in the brain to deter the progression of AD162. One promising intervention is the use of the incretin hormone glucagon-like peptide 1 (GLP1) as a treatment for neurodegenerative diseases163. In vivo administration of GLP1 or exendin-4, a more stable analogue of GLP1, reduces endogenous levels of amyloid-β40 in the mouse brain and protects against cell death164. In addition, GLP1 and the stable analogue (Val8)GLP1 enhance long-term potentiation (LTP) and reverse the LTP impairment induced by amyloid-β25-35 administration in rodents, which might underlie an improvement in cognitive function165. Most recently, (Val8)GLP1 also prevented amyloid-β40-induced impairment in late-phase LTP, and spatial learning and memory in rodents166. Some evidence also suggests that the desensitization of insulin receptors that occurs in AD can be reversed by activation of GLP1 receptors (GLP1Rs)167. GLP1 binds to GLP1R, which activates diverse signalling pathways, including cyclic AMP, protein kinase A, phospholipase C, phosphatidylinositol 3-kinase, protein kinase C and mitogen-activated protein kinase168–171. GLP1R-deficient mice display an impairment in synaptic plasticity163 and a decrease in the acquisition of contextual learning, a learning deficit that can be reversed following hippocampal gene transfer of Glp1r172. By contrast, overexpression of GLP1R through hippocampal gene transfer markedly enhanced learning and memory in rodents172. Taken together, these studies suggest that the GLP1R represents a novel and promising therapeutic target for AD. Amylin receptor Amylin (also known as islet amyloid polypeptide) is a peptide that was first isolated from amyloid deposits from the pancreatic islets of Langerhans of patients with type 2 diabetes173. Interestingly, human amylin, which acts through the G protein-coupled amylin receptor, possesses amyloidogenic and neurotoxic properties similar to amyloid-β174. Accordingly, treatment of rat neuronal cultures with an amylin receptor antagonist, AC187, attenuates amyloid-β42- and amylin-induced neurotoxicity by blocking caspase activation175. It would be interesting to determine whether treatment with GLP1 could alleviate the cognitive deficits, and to determine the expression levels of GLP1R in this diabetic AD mouse model. Most recently, studies conducted by crossing two T2D mouse models with an AD mouse model have provided further mechanistic insight into the relationship between diabetes and AD, demonstrating that the onset of diabetes exacerbates cognitive dysfuntion in the absence of an elevation in amyloid-β levels and leads to increased cerebrovascular inflammation and amyloid angiopathy176. Conversely, the diabetic AD mice display an accelerated diabetic phenotype relative to the diabetic mouse model alone, suggesting that the amyloid pathology may adversely affect the T2D and vice versa.

 

Concluding remarks numerous drug discovery efforts target the inhibition of amyloid-­β production, the prevention of amyloid­β aggregation and the enhancement of amyloid-­β clearance. Although these may seem to be straightforward biochemical pathways, several feedback loops enhance not only amyloid­β deposition but also its toxicity, clearance and overall impact on memory function and neuronal health. Such feedback loops also imply that a monotherapy will not be sufficient to prevent the progression of AD. based on the discussion above, it is clear that several GPCRs are involved at many stages of AD disease progression (TABle 1). There also seems to be a pathologically reinforcing loop between type 2 diabetes and AD, with GPCRs providing an avenue for therapeutic intervention for both diseases (BOX 2). Drugs that target GPCRs could diversify the symptomatic therapeutic portfolio for AD and potentially provide disease­modifying treatments. In this sense, they complement the current areas of investigation, which are primarily focused on secretase inhibitors77 and amyloid immunotherapy144. Given that the current anti­amyloidogenic therapy under development is considered to be most effective as a preventative measure or in early stages of AD, additional drugs that preferentially enhance cognition will become a necessary complement to treatment, especially as the disease progresses to more advanced stages. In this regard, GPCRs represent the largest therapeutic target in the pharmaceutical industry and provide ample opportunities for AD­related drug development. nevertheless, progress in the field is hampered by the difficulty in developing highly receptor­specific ligands and the adverse side effects of currently available drugs. Recent advances in the GPCR field suggest that a more functional approach towards the classification of GPCRs, which are now organized according to structural similarity, might enhance the therapeutic potential of GPCRs and assist in the development of selective GPCR candidate drugs for AD and many other diseases.

 

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Biochemistry and Dysmetabolism of Aging and Serious Illness

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Biochemistry and Dysmetabolism of Aging and Serious Illness, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Biochemistry and Dysmetabolism of Aging and Serious Illness

Curator: Larry H. Bernstein, MD, FCAP

 

White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer’s Disease

Lauren P. Klosinski, Jia Yao, Fei Yin, Alfred N. Fonteh, Michael G. Harrington, Trace A. Christensen, Eugenia Trushina, Roberta Diaz Brinton
http://www.ebiomedicine.com/article/S2352-3964(15)30192-4/abstract      DOI: http://dx.doi.org/10.1016/j.ebiom.2015.11.002
Highlights
  • •Mitochondrial dysfunction activates mechanisms for catabolism of myelin lipids to generate ketone bodies for ATP production.
  • •Mechanisms leading to ketone body driven energy production in brain coincide with stages of reproductive aging in females.
  • •Sequential activation of myelin catabolism pathway during aging provides multiple therapeutic targets and windows of efficacy.

The mechanisms underlying white matter degeneration, a hallmark of multiple neurodegenerative diseases including Alzheimer’s, remain unclear. Herein we provide a mechanistic pathway, spanning multiple transitions of aging, that links mitochondrial dysfunction early in aging with later age white matter degeneration. Catabolism of myelin lipids to generate ketone bodies can be viewed as an adaptive survival response to address brain fuel and energy demand. Women are at greatest risk of late-onset-AD, thus, our analyses in female brain address mechanisms of AD pathology and therapeutic targets to prevent, delay and treat AD in the sex most affected with potential relevance to men.

 

White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer’s. Age remains the greatest risk factor for Alzheimer’s and the prevalence of age-related late onset Alzheimer’s is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer’s risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer’s and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical.

3. Results

  1. 3.1. Pathway of Mitochondrial Deficits, H2O2 Production and cPLA2 Activation in the Aging Female Brain
  2. 3.2. cPLA2-sphingomyelinase Pathway Activation in White Matter Astrocytes During Reproductive Senescence
  3. 3.3. Investigation of White Matter Gene Expression Profile During Reproductive Senescence
  4. 3.4. Ultra Structural Analysis of Myelin Sheath During Reproductive Senescence
  5. 3.5. Analysis of the Lipid Profile of Brain During the Transition to Reproductive Senescence
  6. 3.6. Fatty Acid Metabolism and Ketone Generation Following the Transition to Reproductive Senescence

 

4. Discussion

Age remains the greatest risk factor for developing AD (Hansson et al., 2006, Alzheimer’s, 2015). Thus, investigation of transitions in the aging brain is a reasoned strategy for elucidating mechanisms and pathways of vulnerability for developing AD. Aging, while typically perceived as a linear process, is likely composed of dynamic transition states, which can protect against or exacerbate vulnerability to AD (Brinton et al., 2015). An aging transition unique to the female is the perimenopausal to menopausal conversion (Brinton et al., 2015). The bioenergetic similarities between the menopausal transition in women and the early appearance of hypometabolism in persons at risk for AD make the aging female a rational model to investigate mechanisms underlying risk of late onset AD.

Findings from this study replicate our earlier findings that age of reproductive senescence is associated with decline in mitochondrial respiration, increased H2O2 production and shift to ketogenic metabolism in brain (Yao et al., 2010, Ding et al., 2013, Yin et al., 2015). These well established early age-related changes in mitochondrial function and shift to ketone body utilization in brain, are now linked to a mechanistic pathway that connects early decline in mitochondrial respiration and H2O2 production to activation of the cPLA2-sphingomyelinase pathway to catabolize myelin lipids resulting in WM degeneration (Fig. 12). These lipids are sequestered in lipid droplets for subsequent use as a local source of ketone body generation via astrocyte mediated beta-oxidation of fatty acids. Astrocyte derived ketone bodies can then be transported to neurons where they undergo ketolysis to generate acetyl-CoA for TCA derived ATP generation required for synaptic and cell function (Fig. 12).

Thumbnail image of Fig. 12. Opens large image

http://www.ebiomedicine.com/cms/attachment/2040395791/2053874721/gr12.sml

Fig. 12

Schematic model of mitochondrial H2O2 activation of cPLA2-sphingomyelinase pathway as an adaptive response to provide myelin derived fatty acids as a substrate for ketone body generation: The cPLA2-sphingomyelinase pathway is proposed as a mechanistic pathway that links an early event, mitochondrial dysfunction and H2O2, in the prodromal/preclinical phase of Alzheimer’s with later stage development of pathology, white matter degeneration. Our findings demonstrate that an age dependent deficit in mitochondrial respiration and a concomitant rise in oxidative stress activate an adaptive cPLA2-sphingomyelinase pathway to provide myelin derived fatty acids as a substrate for ketone body generation to fuel an energetically compromised brain.

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Biochemical evidence obtained from isolated whole brain mitochondria confirms that during reproductive senescence and in response to estrogen deprivation brain mitochondria decline in respiratory capacity (Yao et al., 2009, Yao et al., 2010, Brinton, 2008a, Brinton, 2008b, Swerdlow and Khan, 2009). A well-documented consequence of mitochondrial dysfunction is increased production of reactive oxygen species (ROS), specifically H2O2 (Boveris and Chance, 1973, Beal, 2005, Yin et al., 2014, Yap et al., 2009). While most research focuses on the damage generated by free radicals, in this case H2O2 functions as a signaling molecule to activate cPLA2, the initiating enzyme in the cPLA2-sphingomyelinase pathway (Farooqui and Horrocks, 2006, Han et al., 2003, Sun et al., 2004). In AD brain, increased cPLA2 immunoreactivity is detected almost exclusively in astrocytes suggesting that activation of the cPLA2-sphingomyelinase pathway is localized to astrocytes in AD, as opposed to the neuronal or oligodendroglial localization that is observed during apoptosis (Sun et al., 2004, Malaplate-Armand et al., 2006, Di Paolo and Kim, 2011, Stephenson et al., 1996,Stephenson et al., 1999). In our analysis, cPLA2 (Sanchez-Mejia and Mucke, 2010) activation followed the age-dependent rise in H2O2 production and was sustained at an elevated level.

Direct and robust activation of astrocytic cPLA2 by physiologically relevant concentrations of H2O2 was confirmed in vitro. Astrocytic involvement in the cPLA2-sphingomyelinase pathway was also indicated by an increase in cPLA2 positive astrocyte reactivity in WM tracts of reproductively incompetent mice. These data are consistent with findings from brains of persons with AD that demonstrate the same striking localization of cPLA2immunoreactivity within astrocytes, specifically in the hippocampal formation (Farooqui and Horrocks, 2004). While neurons and astrocytes contain endogenous levels of cPLA2, neuronal cPLA2 is activated by an influx of intracellular calcium, whereas astrocytic cPLA2 is directly activated by excessive generation of H2O2 (Sun et al., 2004, Xu et al., 2003, Tournier et al., 1997). Evidence of this cell type specific activation was confirmed by the activation of cPLA2 in astrocytes by H2O2 and the lack of activation in neurons. These data support that astrocytic, not neuronal, cPLA2 is the cellular mediator of the H2O2 dependent cPLA2-sphingomyelinase pathway activation and provide associative evidence supporting a role of astrocytic mitochondrial H2O2 in age-related WM catabolism.

The pattern of gene expression during the shift to reproductive senescence in the female mouse hippocampus recapitulates key observations in human AD brain tissue, specifically elevation in cPLA2, sphingomyelinase and ceramidase (Schaeffer et al., 2010, He et al., 2010, Li et al., 2014). Further, up-regulation of myelin synthesis, lipid metabolism and inflammatory genes in reproductively incompetent female mice is consistent with the gene expression pattern previously reported from aged male rodent hippocampus, aged female non-human primate hippocampus and human AD hippocampus (Blalock et al., 2003, Blalock et al., 2004, Blalock et al., 2010, Blalock et al., 2011, Kadish et al., 2009, Rowe et al., 2007). In these analyses of gene expression in aged male rodent hippocampus, aged female non-human primate hippocampus and human AD hippocampus down regulation of genes related to mitochondrial function, and up-regulation in multiple genes encoding for enzymes involved in ketone body metabolism occurred (Blalock et al., 2003, Blalock et al., 2004, Blalock et al., 2010, Blalock et al., 2011, Kadish et al., 2009, Rowe et al., 2007). The comparability across data derived from aging female mouse hippocampus reported herein and those derived from male rodent brain, female nonhuman brain and human AD brain strongly suggest that cPLA2-sphingomyelinase pathway activation, myelin sheath degeneration and fatty acid metabolism leading to ketone body generation is a metabolic adaptation that is generalizable across these naturally aging models and are evident in aged human AD brain. Collectively, these data support the translational relevance of findings reported herein.

Data obtained via immunohistochemistry, electron microscopy and MBP protein analyses demonstrated an age-related loss in myelin sheath integrity. Evidence for a loss of myelin structural integrity emerged in reproductively incompetent mice following activation of the cPLA2-sphingomyelinase pathway. The unraveling myelin phenotype observed following reproductive senescence and aging reported herein is consistent with the degenerative phenotype that emerges following exposure to the chemotherapy drug bortezomib which induces mitochondrial dysfunction and increased ROS generation (Carozzi et al., 2010, Cavaletti et al., 2007,Ling et al., 2003). In parallel to the decline in myelin integrity, lipid droplet density increased. In aged mice, accumulation of lipid droplets declined in parallel to the rise in ketone bodies consistent with the utilization of myelin-derived fatty acids to generate ketone bodies. Due to the sequential relationship between WM degeneration and lipid droplet formation, we posit that lipid droplets serve as a temporary storage site for myelin-derived fatty acids prior to undergoing β-oxidation in astrocytes to generate ketone bodies.

Microstructural alterations in myelin integrity were associated with alterations in the lipid profile of brain, indicative of WM degeneration resulting in release of myelin lipids. Sphingomyelin and galactocerebroside are two main lipids that compose the myelin sheath (Baumann and Pham-Dinh, 2001). Ceramide is common to both galactocerebroside and sphingomyelin and is composed of sphingosine coupled to a fatty acid. Ceramide levels increase in aging, in states of ketosis and in neurodegeneration (Filippov et al., 2012, Blazquez et al., 1999, Costantini et al., 2005). Specifically, ceramide levels are elevated at the earliest clinically recognizable stage of AD, indicating a degree of WM degeneration early in disease progression (Di Paolo and Kim, 2011,Han et al., 2002, Costantini et al., 2005). Sphingosine is statistically significantly elevated in the brains of AD patients compared to healthy controls; a rise that was significantly correlated with acid sphingomyelinase activity, Aβ levels and tau hyperphosphorylation (He et al., 2010). In our analyses, a rise in ceramides was first observed early in the aging process in reproductively incompetent mice. The rise in ceramides was coincident with the emergence of loss of myelin integrity consistent with the release of myelin ceramides from sphingomyelin via sphingomyelinase activation. Following the rise in ceramides, sphingosine and fatty acid levels increased. The temporal sequence of the lipid profile was consistent with gene expression indicating activation of ceramidase for catabolism of ceramide into sphingosine and fatty acid during reproductive senescence. Once released from ceramide, fatty acids can be transported into the mitochondrial matrix of astrocytes via CPT-1, where β-oxidation of fatty acids leads to the generation of acetyl-CoA (Glatz et al., 2010). It is well documented that acetyl-CoA cannot cross the inner mitochondrial membrane, thus posing a barrier to direct transport of acetyl-CoA generated by β-oxidation into neurons. In response, the newly generated acetyl-CoA undergoes ketogenesis to generate ketone bodies to fuel energy demands of neurons (Morris, 2005,Guzman and Blazquez, 2004, Stacpoole, 2012). Because astrocytes serve as the primary location of β-oxidation in brain they are critical to maintaining neuronal metabolic viability during periods of reduced glucose utilization (Panov et al., 2014, Ebert et al., 2003, Guzman and Blazquez, 2004).

Once fatty acids are released from myelin ceramides, they are transported into astrocytic mitochondria by CPT1 to undergo β-oxidation. The mitochondrial trifunctional protein HADHA catalyzes the last three steps of mitochondrial β-oxidation of long chain fatty acids, while mitochondrial ABAD (aka SCHAD—short chain fatty acid dehydrogenase) metabolizes short chain fatty acids. Concurrent with the release of myelin fatty acids in aged female mice, CPT1, HADHA and ABAD protein expression as well as ketone body generation increased significantly. These findings indicate that astrocytes play a pivotal role in the response to bioenergetic crisis in brain to activate an adaptive compensatory system that activates catabolism of myelin lipids and the metabolism of those lipids into fatty acids to generate ketone bodies necessary to fuel neuronal demand for acetyl-CoA and ATP.

Collectively, these findings provide a mechanistic pathway that links mitochondrial dysfunction and H2O2generation in brain early in the aging process to later stage white matter degeneration. Astrocytes play a pivotal role in providing a mechanistic strategy to address the bioenergetic demand of neurons in the aging female brain. While this pathway is coincident with reproductive aging in the female brain, it is likely to have mechanistic translatability to the aging male brain. Further, the mechanistic link between bioenergetic decline and WM degeneration has potential relevance to other neurological diseases involving white matter in which postmenopausal women are at greater risk, such as multiple sclerosis. The mechanistic pathway reported herein spans time and is characterized by a progression of early adaptive changes in the bioenergetic system of the brain leading to WM degeneration and ketone body production. Translationally, effective therapeutics to prevent, delay and treat WM degeneration during aging and Alzheimer’s disease will need to specifically target stages within the mechanistic pathway described herein. The fundamental initiating event is a bioenergetic switch from being a glucose dependent brain to a glucose and ketone body dependent brain. It remains to be determined whether it is possible to prevent conversion to or reversal of a ketone dependent brain. Effective therapeutic strategies to intervene in this process require biomarkers of bioenergetic phenotype of the brain and stage of mechanistic progression. The mechanistic pathway reported herein may have relevance to other age-related neurodegenerative diseases characterized by white matter degeneration such as multiple sclerosis.

Blood. 2015 Oct 15;126(16):1925-9.    http://dx.doi.org:/10.1182/blood-2014-12-617498. Epub 2015 Aug 14.
Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias.
Ricciardi MR1, Mirabilii S2, Allegretti M2, Licchetta R2, Calarco A3, Torrisi MR1, Foà R2, Nicolai R4, Peluso G3, Tafuri A1.   Author information
Cancer cells are characterized by perturbations of their metabolic processes. Recent observations demonstrated that the fatty acid oxidation (FAO) pathway may represent an alternative carbon source for anabolic processes in different tumors, therefore appearing particularly promising for therapeutic purposes. Because the carnitine palmitoyl transferase 1a (CPT1a) is a protein that catalyzes the rate-limiting step of FAO, here we investigated the in vitro antileukemic activity of the novel CPT1a inhibitor ST1326 on leukemia cell lines and primary cells obtained from patients with hematologic malignancies. By real-time metabolic analysis, we documented that ST1326 inhibited FAO in leukemia cell lines associated with a dose- and time-dependent cell growth arrest, mitochondrial damage, and apoptosis induction. Data obtained on primary hematopoietic malignant cells confirmed the FAO inhibition and cytotoxic activity of ST1326, particularly on acute myeloid leukemia cells. These data suggest that leukemia treatment may be carried out by targeting metabolic processes.
Oncogene. 2015 Oct 12.   http://dx.doi.org:/10.1038/onc.2015.394. [Epub ahead of print]
Tumour-suppression function of KLF12 through regulation of anoikis.
Godin-Heymann N1, Brabetz S1, Murillo MM1,2, Saponaro M3, Santos CR4, Lobley A5, East P5, Chakravarty P5, Matthews N6, Kelly G5, Jordan S1, Castellano E1, Downward J1,2.  Author information
Suppression of detachment-induced cell death, known as anoikis, is an essential step for cancer metastasis to occur. We report here that expression of KLF12, a member of the Kruppel-like family of transcription factors, is downregulated in lung cancer cell lines that have been selected to grow in the absence of cell adhesion. Knockdown of KLF12 in parental cells results in decreased apoptosis following cell detachment from matrix. KLF12 regulates anoikis by promoting the cell cycle transition through S phase and therefore cell proliferation. Reduced expression levels of KLF12 results in increased ability of lung cancer cells to form tumours in vivo and is associated with poorer survival in lung cancer patients. We therefore identify KLF12 as a novel metastasis-suppressor gene whose loss of function is associated with anoikis resistance through control of the cell cycle.
Mol Cell. 2015 Oct 14. pii: S1097-2765(15)00764-9. doi: 10.1016/j.molcel.2015.09.025. [Epub ahead of print]
PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth.
Montal ED1, Dewi R2, Bhalla K3, Ou L2, Hwang BJ2, Ropell AE4, Gordon C4, Liu WJ3, DeBerardinis RJ5, Sudderth J5, Twaddel W6, Boros LG7, Shroyer KR4,Duraisamy S8, Drapkin R8, Powers RS6, Rohde JM9, Boxer MB9, Wong KK10, Girnun GD11.    Author information
Phosphoenolpyruvate carboxykinase (PEPCK) is well known for its role in gluconeogenesis. However, PEPCK is also a key regulator of TCA cycle flux. The TCA cycle integrates glucose, amino acid, and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. We show here an unexpected role for PEPCK in promoting cancer cell proliferation in vitro and in vivo by increasing glucose and glutamine utilization toward anabolic metabolism. Unexpectedly, PEPCK also increased the synthesis of ribose from non-carbohydrate sources, such as glutamine, a phenomenon not previously described. Finally, we show that the effects of PEPCK on glucose metabolism and cell proliferation are in part mediated via activation of mTORC1. Taken together, these data demonstrate a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation.
Mol Cancer Res. 2015 Oct;13(10):1408-20.   http://dx.doi.org:/10.1158/1541-7786.MCR-15-0048. Epub 2015 Jun 16.
Disruption of Proline Synthesis in Melanoma Inhibits Protein Production Mediated by the GCN2 Pathway.
Kardos GR1, Wastyk HC2, Robertson GP3. Author information
Many processes are deregulated in melanoma cells and one of those is protein production. Although much is known about protein synthesis in cancer cells, effective ways of therapeutically targeting this process remain an understudied area of research. A process that is upregulated in melanoma compared with normal melanocytes is proline biosynthesis, which has been linked to both oncogene and tumor suppressor pathways, suggesting an important convergent point for therapeutic intervention. Therefore, an RNAi screen of a kinase library was undertaken, identifying aldehyde dehydrogenase 18 family, member A1 (ALDH18A1) as a critically important gene in regulating melanoma cell growth through proline biosynthesis. Inhibition of ALDH18A1, the gene encoding pyrroline-5-carboxylate synthase (P5CS), significantly decreased cultured melanoma cell viability and tumor growth. Knockdown of P5CS using siRNA had no effect on apoptosis, autophagy, or the cell cycle but cell-doubling time increased dramatically suggesting that there was a general slowdown in cellular metabolism. Mechanistically, targeting ALDH18A1 activated the serine/threonine protein kinase GCN2 (general control nonderepressible 2) to inhibit protein synthesis, which could be reversed with proline supplementation. Thus, targeting ALDH18A1 in melanoma can be used to disrupt proline biosynthesis to limit cell metabolism thereby increasing the cellular doubling time mediated through the GCN2 pathway.  This study demonstrates that melanoma cells are sensitive to disruption of proline synthesis and provides a proof-of-concept that the proline synthesis pathway can be therapeutically targeted in melanoma tumors for tumor inhibitory efficacy. Mol Cancer Res; 13(10); 1408-20. ©2015 AACR.
J Natl Cancer Inst. 2015 Oct 12;108(1). pii: djv287.   http://dx.doi.org:/10.1093/jnci/djv287.
SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery.
Saxena N1, Maio N1, Crooks DR1, Ricketts CJ1, Yang Y1, Wei MH1, Fan TW1, Lane AN1, Sourbier C1, Singh A1, Killian JK1, Meltzer PS1, Vocke CD1, Rouault TA1, Linehan WM1.  Author information
BACKGROUND:  Mutations in the Fe-S cluster-containing SDHB subunit of succinate dehydrogenase cause familial cancer syndromes. Recently the tripeptide motif L(I)YR was identified in the Fe-S recipient protein SDHB, to which the cochaperone HSC20 binds.
METHODS:   In order to characterize the metabolic basis of SDH-deficient cancers we performed stable isotope-resolved metabolomics in a novel SDHB-deficient renal cell carcinoma cell line and conducted bioinformatics and biochemical screening to analyze Fe-S cluster acquisition and assembly of SDH in the presence of other cancer-causing SDHB mutations.

RESULTS:

We found that the SDHB(R46Q) mutation in UOK269 cells disrupted binding of HSC20, causing rapid degradation of SDHB. In the absence of SDHB, respiration was undetectable in UOK269 cells, succinate was elevated to 351.4±63.2 nmol/mg cellular protein, and glutamine became the main source of TCA cycle metabolites through reductive carboxylation. Furthermore, HIF1α, but not HIF2α, increased markedly and the cells showed a strong DNA CpG island methylator phenotype (CIMP). Biochemical and bioinformatic screening revealed that 37% of disease-causing missense mutations in SDHB were located in either the L(I)YR Fe-S transfer motifs or in the 11 Fe-S cluster-ligating cysteines.

CONCLUSIONS:

These findings provide a conceptual framework for understanding how particular mutations disproportionately cause the loss of SDH activity, resulting in accumulation of succinate and metabolic remodeling in SDHB cancer syndromes.

 

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMPK-mTOR Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

  1. L. Figarola, J. Singhal, J. D. Tompkins, G. W. Rogers, C. Warden, D. Horne, A. D. Riggs, S. Awasthi and S. S. Singhal.

J Biol Chem. 2015 Nov 3, [epub ahead of print]

 

CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation

  1. W. Miller, D. R. Soto-Pantoja, A. L. Schwartz, J. M. Sipes, W. G. DeGraff, L. A. Ridnour, D. A. Wink and D. D. Roberts.

J Biol Chem. 2015 Oct 9, 290 (41): 24858-74.

 

Knockdown of PKM2 Suppresses Tumor Growth and Invasion in Lung Adenocarcinoma

  1. Sun, A. Zhu, L. Zhang, J. Zhang, Z. Zhong and F. Wang.

Int J Mol Sci. 2015 Oct 15, 16 (10): 24574-87.

 

EglN2 associates with the NRF1-PGC1alpha complex and controls mitochondrial function in breast cancer

  1. Zhang, C. Wang, X. Chen, M. Takada, C. Fan, X. Zheng, H. Wen, Y. Liu, C. Wang, R. G. Pestell, K. M. Aird, W. G. Kaelin, Jr., X. S. Liu and Q. Zhang.

EMBO J. 2015 Oct 22, [epub ahead of print]

 

Cancer Res. 2015 Oct 15;75(20):4429-36.    http://dx.doi.org:/10.1158/0008-5472.CAN-15-0074.
Mitochondrial Genetics Regulate Breast Cancer Tumorigenicity and Metastatic Potential.
Feeley KP1, Bray AW1, Westbrook DG1, Johnson LW2, Kesterson RA2, Ballinger SW1, Welch DR3.  Author information   

Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors influence an individual’s predilection for developing metastatic breast cancer. Investigations of tumor latency and metastasis in mice have illustrated differences between inbred strains, but the possibility that mitochondrial genetic inheritance may contribute to such differences in vivo has not been directly tested. In this study, we tested this hypothesis in mitochondrial-nuclear exchange mice we generated, where cohorts shared identical nuclear backgrounds but different mtDNA genomes on the background of the PyMT transgenic mouse model of spontaneous mammary carcinoma. In this setting, we found that primary tumor latency and metastasis segregated with mtDNA, suggesting that mtDNA influences disease progression to a far greater extent than previously appreciated. Our findings prompt further investigation into metabolic differences controlled by mitochondrial process as a basis for understanding tumor development and metastasis in individual subjects. Importantly, differences in mitochondrial DNA are sufficient to fundamentally alter disease course in the PyMT mouse mammary tumor model, suggesting that functional metabolic differences direct early tumor growth and metastatic efficiency. Cancer Res; 75(20); 4429-36. ©2015 AACR.

 

Cancer Lett. 2015 Oct 29. pii: S0304-3835(15)00656-4.    http://dx.doi.org:/10.1016/j.canlet.2015.10.025. [Epub ahead of print]
Carboxyamidotriazole inhibits oxidative phosphorylation in cancer cells and exerts synergistic anti-cancer effect with glycolysis inhibition.
Ju R1, Guo L1, Li J1, Zhu L1, Yu X1, Chen C1, Chen W1, Ye C2, Zhang D3. Author information   

Targeting cancer cell metabolism is a promising strategy against cancer. Here, we confirmed that the anti-cancer drug carboxyamidotriazole (CAI) inhibited mitochondrial respiration in cancer cells for the first time and found a way to enhance its anti-cancer activity by further disturbing the energy metabolism. CAI promoted glucose uptake and lactate production when incubated with cancer cells. The oxidative phosphorylation (OXPHOS) in cancer cells was inhibited by CAI, and the decrease in the activity of the respiratory chain complex I could be one explanation. The anti-cancer effect of CAI was greatly potentiated when being combined with 2-deoxyglucose (2-DG). The cancer cells treated with the combination of CAI and 2-DG were arrested in G2/M phase. The apoptosis and necrosis rates were also increased. In a mouse xenograft model, this combination was well tolerated and retarded the tumor growth. The impairment of cancer cell survival was associated with significant cellular ATP decrease, suggesting that the combination of CAI and 2-DG could be one of the strategies to cause dual inhibition of energy pathways, which might be an effective therapeutic approach for a broad spectrum of tumors.

 

Cancer Immunol Res. 2015 Nov;3(11):1236-47.    http://dx.doi.org:/10.1158/2326-6066.CIR-15-0036. Epub 2015 May 29.
Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies.
Hossain F1, Al-Khami AA2, Wyczechowska D2, Hernandez C2, Zheng L2, Reiss K3, Valle LD4, Trillo-Tinoco J2, Maj T5, Zou W5, Rodriguez PC6, Ochoa AC7.  Author information

Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T-cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies. Cancer Immunol Res; 3(11); 1236-47. ©2015 AACR.

 

Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase

  1. L. Judge, K. M. Owens, S. J. Pollock, C. F. Woeller, T. H. Thatcher, J. P. Williams, R. P. Phipps, P. J. Sime and R. M. Kottmann.

Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15, 309 (8): L879-87.

 

Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH

  1. Yun, E. Mullarky, C. Lu, K. N. Bosch, A. Kavalier, K. Rivera, J. Roper, Chio, II, E. G. Giannopoulou, C. Rago, A. Muley, J. M. Asara, J. Paik, O. Elemento, Z. Chen, D. J. Pappin, L. E. Dow, N. Papadopoulos, S. S. Gross and L. C. Cantley.

Science. 2015 Nov 5, [epub ahead of print]

 

Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells

  1. Zhang, J. Wang, H. Xing, Q. Li, Q. Zhao and J. Li.

Mol Cell Biochem. 2015 Nov 6, [epub ahead of print]

 

J Mol Cell Cardiol. 2015 Oct 23. pii: S0022-2828(15)30073-0.     http://dx.doi.org:/10.1016/j.yjmcc.2015.10.002. [Epub ahead of print]
GRK2 compromises cardiomyocyte mitochondrial function by diminishing fatty acid-mediated oxygen consumption and increasing superoxide levels.
Sato PY1, Chuprun JK1, Ibetti J1, Cannavo A1, Drosatos K1, Elrod JW1, Koch WJ2.    Author information

The G protein-coupled receptor kinase-2 (GRK2) is upregulated in the injured heart and contributes to heart failure pathogenesis. GRK2 was recently shown to associate with mitochondria but its functional impact in myocytes due to this localization is unclear. This study was undertaken to determine the effect of elevated GRK2 on mitochondrial respiration in cardiomyocytes. Sub-fractionation of purified cardiac mitochondria revealed that basally GRK2 is found in multiple compartments. Overexpression of GRK2 in mouse cardiomyocytes resulted in an increased amount of mitochondrial-based superoxide. Inhibition of GRK2 increased oxygen consumption rates and ATP production. Moreover, fatty acid oxidation was found to be significantly impaired when GRK2 was elevated and was dependent on the catalytic activity and mitochondrial localization of this kinase. Our study shows that independent of cardiac injury, GRK2 is localized in the mitochondria and its kinase activity negatively impacts the function of this organelle by increasing superoxide levels and altering substrate utilization for energy production.

 

Br J Pharmacol. 2015 Oct 27. doi: 10.1111/bph.13377. [Epub ahead of print]
All-trans retinoic acid protects against doxorubicin-induced cardiotoxicity by activating the Erk2 signalling pathway.
Yang L1, Luo C2, Chen C1, Wang X1, Shi W1, Liu J1.   Author information     
BACKGROUND AND PURPOSE:

Doxorubicin (Dox) is a powerful antineoplastic agent for treating a wide range of cancers. However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use. It is known that all-trans retinoic acid (ATRA) plays important roles in many cardiac biological processes, however, the protective effects of ATRA on doxorubicin cardiotoxicity remain unknown. Here, we studied the effect of ATRA on doxorubicin cardiotoxicity and underlying mechanisms.

EXPERIMENTAL APPROACHES:

Cellular viability assays, western blotting and mitochondrial respiration analyses were employed to evaluate the cellular response to ATRA in H9c2 cells and primary cardiomyocytes. Quantitative PCR (Polymerase Chain Reaction) and gene knockdown were performed to investigate the underlying molecular mechanisms of ATRA’s effects on doxorubicin cardiotoxicity.

KEY RESULTS:

ATRA significantly inhibited doxorubicin-induced apoptosis in H9c2 cells and primary cardiomyocytes. ATRA was more effective against doxorubicin cardiotoxicity than resveratrol and dexrazoxane. ATRA also suppressed reactive oxygen species (ROS) generation, and restored the expression level of mRNA and proteins in phase II detoxifying enzyme system: Nrf2 (nuclear factor-E2-related factor 2), MnSOD (manganese superoxide dismutase), HO-1 (heme oxygenase1) as well as mitochondrial function (mitochondrial membrane integrity, mitochondrial DNA copy numbers, mitochondrial respiration capacity, biogenesis and dynamics). Both Erk1/2 (extracellular signal-regulated kinase1/2) inhibitor (U0126) and Erk2 siRNA, but not Erk1 siRNA, abolished the protective effect of ATRA against doxorubicin-induced toxicity in H9c2 cells. Remarkably, ATRA did not compromise the anticancer efficacy of doxorubicin in gastric carcinoma cells.

CONCLUSION AND IMPLICATION:

ATRA protected cardiomyocytes against doxorubicin-induced toxicity by activating the Erk2 pathway without compromising the anticancer efficacy of doxorubicin. Therefore, ATRA may be a promising candidate as a cardioprotective agent against doxorubicin cardiotoxicity.

 

Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation

  1. Colak, O. Pougovkina, L. Dai, M. Tan, H. Te Brinke, H. Huang, Z. Cheng, J. Park, X. Wan, X. Liu, W. W. Yue, R. J. Wanders, J. W. Locasale, D. B. Lombard, V. C. de Boer and Y. Zhao.

Mol Cell Proteomics. 2015 Nov 1, 14 (11): 3056-71.

 

Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics

  1. Pancrazi, G. Di Benedetto, L. Colombaioni, G. Della Sala, G. Testa, F. Olimpico, A. Reyes, M. Zeviani, T. Pozzan and M. Costa.

Proc Natl Acad Sci U S A. 2015 Oct 27, 112(45): 13910-5.

 

Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia

  1. E. Hjelm, B. Rollins, F. Mamdani, J. C. Lauterborn, G. Kirov, G. Lynch, C. M. Gall, A. Sequeira and M. P. Vawter.

Mol Neuropsychiatry. 2015 Nov 1, 1 (4): 201-219.

 

Metabolic Reprogramming Is Required for Myofibroblast Contractility and Differentiation

  1. Bernard, N. J. Logsdon, S. Ravi, N. Xie, B. P. Persons, S. Rangarajan, J. W. Zmijewski, K. Mitra, G. Liu, V. M. Darley-Usmar and V. J. Thannickal.

J Biol Chem. 2015 Oct 16, 290 (42): 25427-38.

 

J Biol Chem. 2015 Oct 23;290(43):25834-46.    http://dx.doi.org:/10.1074/jbc.M115.658815. Epub 2015 Sep 4.
Kinome Screen Identifies PFKFB3 and Glucose Metabolism as Important Regulators of the Insulin/Insulin-like Growth Factor (IGF)-1 Signaling Pathway.
Trefely S1, Khoo PS2, Krycer JR3, Chaudhuri R3, Fazakerley DJ3, Parker BL3, Sultani G1, Lee J4, Stephan JP4, Torres E4, Jung K4, Kuijl C4, James DE5,Junutula JR6, Stöckli J7.   Author information

The insulin/insulin-like growth factor (IGF)-1 signaling pathway (ISP) plays a fundamental role in long term health in a range of organisms. Protein kinases including Akt and ERK are intimately involved in the ISP. To identify other kinases that may participate in this pathway or intersect with it in a regulatory manner, we performed a whole kinome (779 kinases) siRNA screen for positive or negative regulators of the ISP, using GLUT4 translocation to the cell surface as an output for pathway activity. We identified PFKFB3, a positive regulator of glycolysis that is highly expressed in cancer cells and adipocytes, as a positive ISP regulator. Pharmacological inhibition of PFKFB3 suppressed insulin-stimulated glucose uptake, GLUT4 translocation, and Akt signaling in 3T3-L1 adipocytes. In contrast, overexpression of PFKFB3 in HEK293 cells potentiated insulin-dependent phosphorylation of Akt and Akt substrates. Furthermore, pharmacological modulation of glycolysis in 3T3-L1 adipocytes affected Akt phosphorylation. These data add to an emerging body of evidence that metabolism plays a central role in regulating numerous biological processes including the ISP. Our findings have important implications for diseases such as type 2 diabetes and cancer that are characterized by marked disruption of both metabolism and growth factor signaling.

 

FASEB J. 2015 Oct 19.    http://dx.doi.org:/pii: fj.15-276360. [Epub ahead of print]
Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle.
Cho Y1, Hazen BC1, Gandra PG1, Ward SR1, Schenk S1, Russell AP1, Kralli A2.  Author information

Skeletal muscle mitochondrial content and oxidative capacity are important determinants of muscle function and whole-body health. Mitochondrial content and function are enhanced by endurance exercise and impaired in states or diseases where muscle function is compromised, such as myopathies, muscular dystrophies, neuromuscular diseases, and age-related muscle atrophy. Hence, elucidating the mechanisms that control muscle mitochondrial content and oxidative function can provide new insights into states and diseases that affect muscle health. In past studies, we identified Perm1 (PPARGC1- and ESRR-induced regulator, muscle 1) as a gene induced by endurance exercise in skeletal muscle, and regulating mitochondrial oxidative function in cultured myotubes. The capacity of Perm1 to regulate muscle mitochondrial content and function in vivo is not yet known. In this study, we use adeno-associated viral (AAV) vectors to increase Perm1 expression in skeletal muscles of 4-wk-old mice. Compared to control vector, AAV1-Perm1 leads to significant increases in mitochondrial content and oxidative capacity (by 40-80%). Moreover, AAV1-Perm1-transduced muscles show increased capillary density and resistance to fatigue (by 33 and 31%, respectively), without prominent changes in fiber-type composition. These findings suggest that Perm1 selectively regulates mitochondrial biogenesis and oxidative function, and implicate Perm1 in muscle adaptations that also occur in response to endurance exercise.-Cho, Y., Hazen, B. C., Gandra, P. G., Ward, S. R., Schenk, S., Russell, A. P., Kralli, A. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle.

 

Cell Death Dis. 2015 Oct 29;6:e1944.    http://dx.doi.org:/10.1038/cddis.2015.306.
A conserved MADS-box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells.
Mughal W1,2, Nguyen L2, Pustylnik S3, da Silva Rosa SC1,2, Piotrowski S1,2, Chapman D2,4, Du M3, Alli NS3, Grigull J3,5, Halayko AJ6,7, Aliani M8, Topham MK9, Epand RM10, Hatch GM2,11, Pereira TJ2,11, Kereliuk S2,11, McDermott JC3, Rampitsch C12, Dolinsky VW2,11, Gordon JW1,2,4.   Author information
Exposure to metabolic disease during fetal development alters cellular differentiation and perturbs metabolic homeostasis, but the underlying molecular regulators of this phenomenon in muscle cells are not completely understood. To address this, we undertook a computational approach to identify cooperating partners of the myocyte enhancer factor-2 (MEF2) family of transcription factors, known regulators of muscle differentiation and metabolic function. We demonstrate that MEF2 and the serum response factor (SRF) collaboratively regulate the expression of numerous muscle-specific genes, including microRNA-133a (miR-133a). Using tandem mass spectrometry techniques, we identify a conserved phosphorylation motif within the MEF2 and SRF Mcm1 Agamous Deficiens SRF (MADS)-box that regulates miR-133a expression and mitochondrial function in response to a lipotoxic signal. Furthermore, reconstitution of MEF2 function by expression of a neutralizing mutation in this identified phosphorylation motif restores miR-133a expression and mitochondrial membrane potential during lipotoxicity. Mechanistically, we demonstrate that miR-133a regulates mitochondrial function through translational inhibition of a mitophagy and cell death modulating protein, called Nix. Finally, we show that rodents exposed to gestational diabetes during fetal development display muscle diacylglycerol accumulation, concurrent with insulin resistance, reduced miR-133a, and elevated Nix expression, as young adult rats. Given the diverse roles of miR-133a and Nix in regulating mitochondrial function, and proliferation in certain cancers, dysregulation of this genetic pathway may have broad implications involving insulin resistance, cardiovascular disease, and cancer biology.

 

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Studying Alzheimer’s biomarkers in Down syndrome

Posted in Alzheimer's Disease, Behavior, Behavioral Genetics, Biomarkers & Medical Diagnostics, Cerebrovascular and Neurodegenerative Diseases, Child and Adolescent Psychiatry, Clinical & Translational, Clinical Diagnostics, Curation, Diagnostics and Lab Tests, Disease Biology, Etiology, Gene Regulation, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human aging, Innovations in Neurophysiology & Neuropsychology, Neurodegenerative Diseases, Neurological Diseases, Nuclear Medicine, tagged , on November 18, 2015| Leave a Comment »

Studying Alzheimer’s biomarkers in Down syndrome

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

NIH supports new studies to find Alzheimer’s biomarkers in Down syndrome

Groundbreaking initiative will track dementia onset, progress in Down syndrome volunteers

http://www.nih.gov/news-events/news-releases/nih-supports-new-studies-find-alzheimers-biomarkers-down-syndrome

 

The National Institutes of Health has launched a new initiative to identify biomarkers and track the progression of Alzheimer’s in people with Down syndrome. Many people with Down syndrome have Alzheimer’s-related brain changes in their 30s that can lead to dementia in their 50s and 60s. Little is known about how the disease progresses in this vulnerable group. The NIH Biomarkers of Alzheimer’s Disease in Adults with Down Syndrome Initiative will support teams of researchers using brain imaging, as well as fluid and tissue biomarkers in research that may one day lead to effective interventions for all people with dementia.

The studies will be funded by the National Institute on Aging (NIA) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both part of NIH. The institutes are jointly providing an estimated $37 million over five years to two highly collaborative projects, which enlist a number of leading researchers to the effort. To advance Alzheimer’s research worldwide, the teams will make their data and samples freely available to qualified researchers.

“This is the first large-scale Alzheimer’s biomarker endeavor to focus on this high-risk group,” said Laurie Ryan, Ph.D., chief of the Dementias of Aging Branch in NIA’s Division of Neuroscience, which leads NIH research on Alzheimer’s.  “Much like the long-established Alzheimer’s Disease Neuroimaging Initiative, the goal of this initiative is to develop biomarker measures that signal the onset and progression of Alzheimer’s in people with Down syndrome. Hopefully, one day, we will also use these biomarkers to determine the effectiveness of promising treatments.”

The link between Alzheimer’s and Down syndrome is well-known. People with Down syndrome are born with an extra copy of chromosome 21, which contains the amyloid precursor protein gene. This gene plays a role in the production of harmful amyloid plaque, sticky clumps that build up outside neurons in Alzheimer’s disease. Having three copies of this gene is a known risk factor for early-onset Alzheimer’s that can occur in people in their 30s, 40s and 50s. By middle age, most but not all adults with Down syndrome develop signs of Alzheimer’s, and a high percentage go on to develop symptoms of dementia as they age into their 70s.

The initiative establishes funding for two research teams that will pool data and standardize procedures, increase sample size, and collectively analyze data that will be made widely available to the research community. The teams will employ an array of biomarkers to identify and track Alzheimer’s-related changes in the brain and cognition for over 500 Down syndrome volunteers, aged 25 and older. The measures include:

  • Positron emission tomography (PET) scans that track levels of amyloid and glucose (energy used by brain cells); MRI of brain volume and function; and levels of amyloid and tau in cerebrospinal fluid and blood;
  • Blood tests to identify biomarkers in blood, including proteins, lipids and markers of inflammation;
  • Blood tests to collect DNA for genome-wide association studies that identify the genetic factors that may confer risk, or protect against, developing Alzheimer’s;
  • Evaluations of medical conditions and cognitive and memory tests to determine levels of function and monitor any changes;
  • For the first time in people with Down syndrome, PET brain scans that detect levels of tau, the twisted knots of protein within brain cells that are a hallmark Alzheimer’s disease.

Aside from earlier onset, Alzheimer’s in people with Down syndrome is similar to Alzheimer’s in others. The first symptom may be memory loss, although people with Down syndrome initially tend to show behavior changes and problems with walking.

“Over the past 30 years, the average lifespan of people with Down syndrome has doubled to 60 years—a  bittersweet achievement when faced with the possibility of developing Alzheimer’s,” said Melissa Parisi, M.D., Ph.D., chief of the NICHD Intellectual and Developmental Disabilities Branch, which leads NIH’s Down syndrome research. “There is much to learn about Alzheimer’s in Down syndrome, and we’re hopeful that these new projects will provide some answers. One mystery we hope to solve is whether or not the disease progresses at a faster rate in this group.”

Parisi noted that research into Alzheimer’s in Down syndrome is a key focus of the National Plan to Address Alzheimer’s Disease(link is external), which calls for improved care for specific populations that are unequally burdened by the disease, including people with Down syndrome, and for increased research that may lead to possible Alzheimer’s therapies.

Benjamin Handen, Ph.D., Department of Psychiatry, University of Pittsburgh, heads a team that involves investigators and data from: Banner Alzheimer’s Institute, Phoenix; Cambridge University, England; Alzheimer’s Disease Cooperative Study, San Diego; Laboratory of Neuro Imaging, University of Southern California, Los Angeles. Nicole Schupf, Ph.D., Columbia University Medical Center, New York City, leads a team involving investigators at: University of California, Irvine; Kennedy Krieger Institute/Johns Hopkins University, Baltimore; Massachusetts General Hospital/Harvard University, Boston; and the University of North Texas Health Sciences Center, Fort Worth.

Learn more about this topic at https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-people-down-syndrome.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s website at http://www.nichd.nih.gov.

About the National Institute on Aging: The NIA leads the federal government effort conducting and supporting research on aging and the health and well-being of older people. It provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimer’s Disease Education and Referral (ADEAR) Center at www.nia.nih.gov/alzheimers.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

 

 

NATIONAL PLAN TO ADDRESS ALZHEIMER’S DISEASE: 2015 UPDATE

pdf-document/national-plan-address-alzheimer%E2%80%99s-disease-2015-update (58 PDF pages)

Introduction

Vision Statement

National Alzheimer’s Project Act

Alzheimer’s Disease and Related Dementias

The Challenges

Framework and Guiding Principles

Goals as Building Blocks for Transformation

2015 Update

 

The Connection between Down Syndrome and Alzheimer’s Disease

Many, but not all, people with Down syndrome develop Alzheimer’s disease when they get older. Alzheimer’s is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out simple tasks.

Alzheimer’s disease is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning—thinking, remembering, and reasoning—and behavioral abilities to such an extent that it interferes with a person’s daily life and activities.

People with Down syndrome are born with an extra copy of chromosome 21, which carries the APP gene. This gene produces a specific protein called amyloid precursor protein (APP). Too much APP protein leads to a buildup of protein clumps called beta-amyloid plaques in the brain. By age 40, almost all people with Down syndrome have these plaques, along with other protein deposits, called tau tangles, which cause problems with how brain cells function and increase the risk of developing Alzheimer’s dementia.

However, not all people with these brain plaques will develop the symptoms of Alzheimer’s. Estimates suggest that 50 percent or more of people with Down syndrome will develop dementia due to Alzheimer’s disease as they age into their 70s.

Alzheimer’s Disease Symptoms

Many people with Down syndrome begin to show symptoms of Alzheimer’s disease in their 50s or 60s. But, like in all people with Alzheimer’s, changes in the brain that lead to these symptoms are thought to begin at least 10 years earlier. These brain changes include the buildup of plaques and tangles, the loss of connections between nerve cells, the death of nerve cells, and the shrinking of brain tissue (called atrophy).

The risk for Alzheimer’s disease increases with age, so it’s important to watch for certain changes in behavior, such as:

  • increased confusion
  • short-term memory problems (for example, asking the same questions over and over)
  • reduction in or loss of ability to do everyday activities

Other possible symptoms of Alzheimer’s dementia are:

  • seizures that begin in adulthood
  • problems with coordination and walking
  • reduced ability to pay attention
  • behavior and personality changes, such as wandering and being less social
  • decreased fine motor control
  • difficulty finding one’s way around familiar areas

Currently, Alzheimer’s disease has no cure, and no medications have been approved to treat Alzheimer’s in people with Down syndrome.

Down Syndrome and Alzheimer’s Disease Research

Alzheimer’s can last several years, and symptoms usually get worse over time.  Scientists are working hard to understand why some people with Down syndrome develop dementia while others do not. They want to know how Alzheimer’s disease begins and progresses, so they can develop drugs or other treatments that can stop, delay, or even prevent the disease process.

Research in this area includes:

  • Basic studies to improve our understanding of the genetic and biological causes of brain abnormalities that lead to Alzheimer’s
  • Observational research to measure cognitive changes in people over time
  • Studies of biomarkers (biological signs of disease), brain scans, and other tests that may help diagnose Alzheimer’s—even before symptoms appear—and show brain changes as people with Down syndrome age
  • Clinical trials to test treatments for dementia in adults with Down syndrome. Clinical trials are best the way to find out if a treatment is safe and effective in people.

 

Alzheimers Disease Neuroimaging Initiative (ADNI)

A public-private partnership, the purpose of ADNI is to develop a multisite, longitudinal, prospective, naturalistic study of normal cognitive aging, mild cognitive impairment (MCI), and early Alzheimer’s disease as a public domain research resource to facilitate the scientific evaluation of neuroimaging and other biomarkers for the onset and progression of MCI and Alzheimer’s disease.

Dr. Laurie Ryan of the NIA gives a brief overview of ADNI in this video:

https://youtu.be/0rBVe0Fwnik

Dr. Thomas Obisesan of Howard University, an ADNI study participant, and a study companion describe ADNI and what it’s like to be involved in the study

https://youtu.be/rK1yWvvHHl8

Learn more about this topic at https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-people-down-syndrome.

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New Alzheimer’s Protein – AICD

Posted in Alzheimer's Disease, Etiology, Innovations, Neurodegenerative Diseases, Neurological Diseases, Neuroscience, Proteins, Proteomics, Stem Cells for Regenerative Medicine, tagged , on November 13, 2015| Leave a Comment »

New Alzheimer’s Protein – AICD

Larry H. Bernstein, MD, FCAP, Curator

LPBI

SfN 2015 Recap: The Role of Synapses, Neural Networks in Alzheimer’s

Stephanie Guzowski, Editor, Drug Discovery & Development

http://www.biosciencetechnology.com/news/2015/11/sfn-2015-recap-role-synapses-neural-networks-alzheimers

Cognition and behavior rely on communication between individual neurons and extensive interactions between neural networks. But when synaptic dysfunction occurs, the results can be dire, leading to neurodegenerative symptoms in Alzheimer’s disease.

“The brain is the seed of our personal identity,” said Valina Dawson, Ph.D., director of neurogeneration and stem cell programs at Johns Hopkins University in Baltimore, Maryland. “It allows us to interact with our world but when things go wrong in the brain, it’s disastrous for the individual as well as the family.

http://www.biosciencetechnology.com/sites/biosciencetechnology.com/files/bt1511_steph_perineuronal%20nets_SfN.jpg

“Our ability to treat these diseases is limited at the moment. We need new insight into what goes wrong.”

A lesser-known protein

Researchers, for years, have targeted amyloid beta (Aβ) in attempts to halt the progression of Alzheimer’s disease, and have recently, shown increased interest in the protein, tau.

But Paula Pousinha, Ph.D., at the French National Centre for Scientific Research, has focused her research on a lesser-known protein fragment: amyloid precursor protein intracellular domain (AICD). AICD is a fragment of amyloid precursor protein (APP), which is formed at the same time as Aβ in the brain. New evidence suggests that in addition to Aβ, AICD also disrupts communication between neurons during the progression of Alzheimer’s disease. Pousinha presented thesepublished findings at this year’s Society for Neuroscience (SfN) conference, which took place from October 17 to 21 in Chicago.

“Although AICD has been known for more than 10 years, it has been poorly studied,” said Pousinha.
Crtl 1-Venus. Fusion of a fluorescent protein to small link proteins in the PNN allows tracking of PNN dynamics over time. Credit: S.F. Palida et al.

Pousinha’s research team demonstrated that overexpressing AICD levels with AAV vector in rats’ brains “perturbs neuronal communication in the hippocampus,” a key structure necessary in forming memories and an area earliest affected in Alzheimer’s disease.“In normal animals, if we apply to these neurons a high-frequency stimulation, afterward the neurons are stronger,” said Pousinha. “Neurons where we overexpressed AICD failed to have this potentization.”

Pousinha doesn’t negate the importance of Aβ in the development of neurodegenerative diseases. “Our study doesn’t exclude the pathological effects of Aβ,” she said. “We believe that Alzheimer’s disease is much more complex and has more than one candidate that has implications.

“It’s very important for the scientific community to understand the role of all these APP fragments of neuroinflammation — different pieces of the puzzle of how we can stop the disease progression.”

How do memories persist in the brain long term?

New research, also presented at this year’s SfN, has implications for understanding memory to develop treatments for Alzheimer’s disease and dementias. Sakina Palida, a graduate student at the University of California, San Diego found that localized modifications in the perineuronal net (PNN) at synapses could be a mechanism by which information is stably encoded and preserved in the brain over time.

“We still don’t understand how we stably encode and store memories in our brains for up to our entire lifetimes,” said Palida. The prevailing idea on how memories are maintained over time generally focus on postsynaptic proteins, said Palida. “But the problem with looking at intracellular synaptic proteins is that the majority turn over rapidly, of hours to at most a few days. So they’re very unstable.”

So, Palida and her team identified PNN as an ideal substrate for long-term memory. “Kind of like how you carve into stone — stone is a stable substrate — you retain the information regardless of what comes and goes over it.” They demonstrated that individual PNN proteins are highly stable, and that the PNN is locally degraded when synapses are strengthened.

Cord Blood Cells As a Potential Treatment for Alzheimer’s Disease

November 12, 2015 by mburatov

https://beyondthedish.wordpress.com/2015/11/12/cord-blood-cells-as-a-potential-treatment-for-alzheimers-disease/

Jared Ehrhart from the University of South Florida, who also serves as the Director of Research and Development at Saneron CCEL Therapeutics Inc, and his coworkers have shown that cells from umbilical cord blood can not only improve the health of mice that have an experimental form of Alzheimer’s disease (AD), but these can also be administered intravenously, which is safer and easier than other more invasive procedures.

Laboratory mice can be engineered to harbor mutations that can cause a neurodegenerative disease that greatly resembles human AD. One such mouse is the PSAPP mouse that harbors two mutations that are known to cause an inherited, early-onset form of AD in humans. By placing both mutations in the same mouse, the animal forms the characteristic protein plaques more rapidly and shows significant AD symptoms and brain pathology.

Ehrhart used PSAPP mice to test the ability of human umbilical cord blood to ameliorate the symptoms of AD. He injected one million Human Umbilical Cord Blood Cells (HUCBCs) into the tail veins of PSAPP mice and 2.2 million into the tail veins of Sprague-Dawley rats. Then he harvested their tissues at 24 hours, 7 days, and 30 days after injection. Then Ehrhart and his team used a variety of techniques to detect the presence of the HUCBCs.

Interestingly, the HUCBCs were able to cross the blood-brain barrier and take up residence in the brain. The cells remained in the brain and survived there for up to 30 days and did not promote the growth of any tumors.

Several studies have shown that the administration of HUCBCs to mice with a laboratory form of AD can improve the cognitive abilities of those mice (see Darlington D, et al., Cell Transplant. 2015;24(11):2237-50; Banik A, et al., Behav Brain Res. 2015 Sep 15;291:46-59; Darlington D, et al., Stem Cells Dev. 2013 Feb 1;22(3):412-21). However, in such cases it is essential to establish that the administered cells actually found their way to the site of damage and exerted a regenerative response.

Even though Ehrhart and his troop found that the intravenously administered HUCBCs were widely distributed throughout the bodies of the animals, they persisted in the central nervous system for up to one month after they were injected. In the words of this publication, which appeared in Cell Transplantation, the HUCBCs were “broadly detected in both in the brain and several peripheral organs, including the liver, kidneys, and bone marrow.”. The fact that such a minimally invasive procedure like intravenous injection can effectively introduce these cells into the bodies of the PSAPP mice and still produce a significant therapeutic effect is a significant discovery.

Ehrhart and his colleagues concluded that HUCBCs might provide therapeutic effects by modulating the inflammation that tends to accompany the onset of AD. Furthermore, these cells do not need to be delivered by means of an invasive procedure like intracerebroventricular injection. Furthermore, even though HUCBCs were detected in other organs, their numbers in those places was not excessive and the ability of the HUCBCs to cross the blood-brain barrier suggests that these cells might serve as safe, effective therapeutic agents for AD patients some day.
Crtl1-Venus Neurons. Tracking PNN dynamics in live cells, in mouse brain tissue. (Credit: S.F. Palida et al.)

And the team also demonstrated that mice lacking enzymes that degrade the PNN have deficient long-term, but not short-term, memory. “Which is a really exciting new result,” said Palida.

To track the PNN in live animals, Palida and her team fused a fluorescent protein to a small link protein in the PNN to allow tracking of PNN dynamics in real time. They also monitored PNN degradation in live cells after stimulating neurons with brain-derived neurotrophic factor (BDNF), a chemical secreted in the nervous system to enhance signaling — and observed localized degradation of the PNN at some newly formed synapses.

What’s next? “We’re currently making transgenic animals to express this protein, which would allow us to monitor PNN dynamics simultaneously with synaptic dynamics in a live animal brain, and really investigate this hypothesis further,” said Palida.

TOPICS  ANIMAL STUDIES  NEUROSCIENCE  EXCLUSIVE  RESEARCH EXCHANGE

Increased APP intracellular domain (AICD) production perturbs synaptic signal integration via increased NMDAR function

*Paula A Pousinha1 Pubmed Elisabeth Raymond1 Pubmed Xavier Mouska1 Pubmed Michael Willem2 Pubmed Hélène Marie1 Pubmed

http://sfn15.hubbian.com/id_8702

Alzheimer’s disease (AD) is a neurodegenerative disease that begins as mild short-term memory deficits and culminates in total loss of cognition and executive functions. The main culprit of the disease, resulting from Amyloid-Precursor Protein (APP) processing, has been thought to be amyloid-b peptide (Ab). However, despite the genetic and cell biological evidence that supports the amyloid cascade hypothesis, it is becoming clear that AD etiology is complex and that Ab alone is unable to account for all aspects of AD [Pimplikar et al. J Neurosci.30: 14946. 2010]. Gamma-secretase not only liberates Ab, but also its C-terminal intracellular counterpart called APP intracellular domain (AICD) [Passer. et al. JAlzheimers Dis.2: 289-301. 2000], which is known to also accumulate in AD patient’s brain [Ghosal et al. PNAS.106:18367. 2009], but surprisingly little is known about its functions in the hippocampus. To address this crucial issue, we increased AICD production in vivo in adult CA1 pyramidal neurons, mimicking the human pathological condition. Different ex-vivo electrophysiological and pharmacological approaches, including double- patch of neighbor neurons were used. We clearly demonstrate that in vivo AICD production increases synaptic NMDA receptor currents. This causes a frequency-dependent disruption of synaptic signal integration, leading to impaired long-term potentiation, which we were able to rescue by different pharmacological approaches. Our results provide convincing and entirely novel evidence that increased in vivo production of AICD is enough, per se, to cause synaptic dysfunction in CA1 hippocampal neurons.

Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid-β-associated neuropathology in Alzheimer mice.

Darlington D1, Deng J, Giunta B, Hou H, Sanberg CD, Kuzmin-Nichols N, Zhou HD, Mori T, Ehrhart J, Sanberg PR, Tan J.

Stem Cells Dev. 2013 Feb 1;22(3):412-21. doi: 10.1089/scd.2012.0345. Epub 2012 Sep 5.

Alzheimer’s disease (AD) is the most common progressive age-related dementia in the elderly and the fourth major cause of disability and mortality in that population. The disease is pathologically characterized by deposition of β-amyloid plaques neurofibrillary tangles in the brain. Current strategies for the treatment of AD are symptomatic only. As such, they are less than efficacious in terms of significantly slowing or halting the underlying pathophysiological progression of the disease. Modulation by cell therapy may be new promising disease-modifying therapy. Recently, we showed reduction in amyloid-β (Aβ) levels/β-amyloid plaques and associated astrocytosis following low-dose infusions of mononuclear human umbilical cord blood cells (HUCBCs). Our current study extended our previous findings by examining cognition via (1) the rotarod test, (2) a 2-day version of the radial-arm water maze test, and (3) a subsequent observation in an open pool platform test to characterize the effects of monthly peripheral HUCBC infusion (1×10(6) cells/μL) into the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) from 6 to 12 months of age. We show that HUCBC therapy correlates with decreased (1) cognitive impairment, (2) Aβ levels/β-amyloid plaques, (3) amyloidogenic APP processing, and (4) reactive microgliosis after a treatment of 6 or 10 months. As such, this report lays the groundwork for an HUCBC therapy as potentially novel alternative to oppose AD at the disease-modifying level.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549624/bin/fig-2.jpg

Alzheimer’s disease (ad) is the most common progressive age-related dementia, and is pathologically characterized by the deposition of amyloid-β peptide (Aβ) as amyloid plaques in the brain parenchyma and neurofibrillary tangles (NFTs) within neurons. As a result of the atrophy that occurs in both cortical and subcortical regions, patients suffer cognitive and emotional dysregulation leading eventually to an inability to perform acts of daily living independently and safely. In fact, AD has emerged as a national and international pandemic. According to the World Alzheimer Report 2010, dementia patients account for 35.6 million in worldwide, and are expected to increase to 65.7 million by 2030 and 115.4 million by 2050. Currently, the number of AD patients is around 1% of the world’s gross domestic product. Therefore, it is becoming increasingly evident that a more effective treatment or prophylaxes are needed in the near future. This is because Aβ plaques are potent activators of both microglia and astrocytes—central nervous system (CNS) resident immuno-competent cells that respond to cerebral amyloidosis by chronic, pro-inflammatory activation, also known as “inflammaging” (see review [1]). While it was once thought that activation of microglia and astrocytes in AD brains was an epiphenomenon and not a pathoetiological contributor to AD, more recent studies implicate this Aβ-mediated inflammatory cascade as an etiological perpetrator of AD. For example, therapeutic strategies aimed at manipulating this inflammatory cascade, including Aβ immunization, non-steroidal anti-inflammatory drugs, and modulation of microglial activation, are all able to reduce AD-like pathology and improve cognitive impairments in AD transgenic mouse models [2] and, in some cases, reduce AD pathology in humans [3].

While it is true that no model fully recapitulates AD, transgenic animal models pose novel insights into the pathophysiology of Aβ toxicity. This is especially so with regards to the effects of various Aβ species and the probable pathogenic role of Aβ oligomers [4]. In the PSAPP mouse model of cerebral amyloidosis (bearing mutant human APPsw and presenilin-1 transgenes), there are large numbers of compact Aβ plaques in the hippocampus and cerebral cortex. These mice demonstrate greatly accelerated β-amyloid deposition compared with Tg APPsw mice that is apparent as early as 16 weeks of age [5]. Concurrently, they show increased levels of both Aβ1–40 and Aβ1–42 in their parenchyma and a reduced performance of spatial working memory in the period preceding overt Aβ deposition [5]. Such findings support a critical role of Aβ1–42 in the pathogenesis of AD and suggest a neurotoxic effect of soluble forms of Aβ as well [6].

Human umbilical cord blood cells (HUCBCs) have a unique immunomodulatory potential. Therapeutic benefits derived from HUCBC treatment have been suggested to arise from modulation of peripheral inflammatory processes, which in turn affects inflammation in the brain parenchyma, and the mobilization of adult stem cells from the bone marrow (BM) [7–11]. Indeed, in the animal model of stroke, HUCBCs have been shown to promote a strong anti-inflammatory T helper 2 (Th2) response [7], as opposed to the deleterious proinflammatory T helper cell type 1 (Th1) response. Interestingly, this observation was seen in conjunction with reduced infarct volume and very importantly with rescue of neurological deficits [7,12–14].

…………

HUCBC studies done in vitro have shown that these cells secrete soluble factors that have salutary effects [16,58]. Cultured HUCBC supernatants, for example, stimulate survival of neural cells and peripheral blood mononuclear cells cultured under conditions designed to induce cell stress and limit protein synthesis [12]. Moreover, HUCBCs have the capacity to stimulate generation of a vast amount of cytokines and neurotrophic factors that modify inflammatory responses, including IL-11, CSF-1, NGF, and thrombopoietin [7,22,23]. It has been reported that HUCBC entry into the brain is not required to promote neuroprotection [59]. According to the report just outlined, recovery following brain injury is mediated through peripheral anti-inflammatory responses resulting in brain recovery [9]. This is in accord with our results that indicated more of a peripheral, HUCBC-mediated CNS affect, since the cells were not detected in the mouse brain for any significant amount of time.

On the other hand, it should be noted that it has been shown that after irradiation, peripheral macrophages are able to penetrate the brain and mitigate cerebral amyloidosis in AD mice, implying that hematogenously derived macrophages are efficient at phagocytosing and clearing Aβ deposits [18]. Nevertheless, earlier reports have shown that Aβ can also be phagocytosed or cleared by brain-resident microglia [58,60,61].

In the current experimental paradigm, we did not detect the presence of brain-infiltrating macrophages. Specifically, we stained for CD45 (a marker for both macrophages and microglia), and observed that in and around Aβ plaques there were process-bearing cells that morphologically resembled microglia. Further, vascular “cuffing” that would suggest the presence of infiltrating macrophages that are frequently observed in other CNS inflammatory conditions, such as experimental autoimmune encephalomyelitis [62], was not detected. Also, given the difficulties inherent to distinguishing macrophages from microglia, and the ease of peripheral macrophages to engraft into the brain, as well as changes of microglial phenotype after brain injury [63], it remains possible that peripheral macrophages contribute to decreased cerebral amyloidosis after treatment with HUCBCs.

In this report, we have demonstrated that HUCBC infusion decreases Aβ/β-amyloid pathology in the brain parenchyma, reduces brain inflammation evidenced by reduction of activated microglia, and improves cognitive impairments associated with the AD-like pathology in PSAPP mice. These HUCBC-imparted beneficial effects, which correlate with increased brain-to-blood efflux of Aβ and a shift from proinflammatory Th1 to anti-inflammatory Th2 cytokines both in the brain and in the periphery, are similar to what we observed in previous studies after Aβ immunization [64–66]. When taken together, our results provide the basis for a novel immunomodulatory strategy for AD using HUCBCs. While the exact mechanism of efficacy of multiple low-dose HUCBC infusions in AD patients is currently being elucidated, further studies investigating which HUCBC secreted factors are capable of modulating neuroinflammation, reducing AD-like pathology, and rescuing cognitive impairments will need to be explored.

GEN News Highlights    Nov 13, 2015      Alzheimer’s Drug Candidate Also Reverses Effects of Aging

http://www.genengnews.com/gen-news-highlights/alzheimer-s-drug-candidate-also-reverses-effects-of-aging/81251974/

  • Scientists at the Salk Institute say they have found that an experimental drug candidate aimed at combating Alzheimer’s disease has a host of unexpected anti-aging effects in animals.

    The Salk team expanded upon their previous development of a drug candidate, called J147, which takes a different tack by targeting Alzheimer’s major risk factor: old age. In the new work, the team showed that J147 worked well in a mouse model of aging not typically used in Alzheimer’s research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain and other improved physiological features.

    The team’s study (“A comprehensive multiomics approach toward understanding the relationship between aging and dementia”) is published in Aging.

    “Initially, the impetus was to test this drug in a novel animal model that was more similar to 99 percent of Alzheimer’s cases,” says Antonio Currais, Ph.D., the lead author and a member of the Schubert Cellular Neurobiology Laboratory at Salk. “We did not predict we’d see this sort of anti-aging effect, but J147 made old mice look like they were young, based upon a number of physiological parameters.”

    “While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), none have proven effective in the clinic,” says David Schubert, Ph.D., senior author of the study.

    Several years ago, Dr. Schubert and his colleagues began to approach the treatment of the disease from a new angle. Rather than target amyloid, the lab decided to zero in old age. Using cell-based screens against old age-associated brain toxicities, they synthesized J147.

    Previously, the team found that J147 could prevent and even reverse memory loss and Alzheimer’s pathology in mice that have a version of the inherited form of Alzheimer’s, the most commonly used mouse model. However, this form of the disease comprises only about 1% of Alzheimer’s cases. For everyone else, old age is the primary risk factor, according to Dr. Schubert. The team wanted to explore the effects of the drug candidate on a breed of mice that age rapidly and experience a version of dementia that more closely resembles the age-related human disorder.

    In this latest work, the researchers used a comprehensive set of assays to measure the expression of all genes in the brain, as well as over 500 small molecules involved with metabolism in the brains and blood of three groups of the rapidly aging mice. The three groups of rapidly aging mice included one set that was young, one set that was old, and one set that was old but fed J147 as they aged.

    The old mice that received J147 performed better on memory and other tests for cognition and also displayed more robust motor movements. The mice treated with J147 also had fewer pathological signs of Alzheimer’s in their brains. Importantly, because of the large amount of data collected on the three groups of mice, it was possible to demonstrate that many aspects of gene expression and metabolism in the old mice fed J147 were very similar to those of the young animals. These included markers for increased energy metabolism, reduced brain inflammation and reduced levels of oxidized fatty acids in the brain.

    Another notable effect was that J147 prevented the leakage of blood from the microvessels in the brains of old mice. “Damaged blood vessels are a common feature of aging in general, and in Alzheimer’s, it is frequently much worse,” points out Dr. Currais.

    While these studies represent a new and exciting approach to Alzheimer’s drug discovery and animal testing in the context of aging, the only way to demonstrate the clinical relevance of the work is to move J147 into clinical trials for Alzheimer’s disease, note the researchers.

    “If proven safe and effective for Alzheimer’s, the apparent anti-aging effect of J147 would be a welcome benefit,” adds Dr. Schubert. The team aims to begin human trials next year.

Curry Derivative J147 Beats Aricept for Alzheimer’s

Curry (Photo: Wikimedia)
Salk Institute’s J147 is a derivative of turmeric, a spice used in  curry. It beat Aricept (donepezil) in several memory tests. It may also benefit Parkinson’s, Huntington’s, ALS & vascular dementia. Learn how it quickly reverses memory deficits and slows Alzheimer’s in mice.

LA JOLLA, CA—A drug developed by scientists at the Salk Institute for Biological Studies, known as J147, reverses memory deficits and slows Alzheimer’s disease in aged mice following short-term treatment.

J147 was developed at Salk in the laboratory of David Schubert, a professor in the Cellular Neurobiology Laboratory. He said,

“It’s been known for a long time that people in India don’t get very much Alzheimer’s relative to what happens in the United States and the rest of the world.

“One of the curiosities about the diet in India is that they eat a lot of curry. A major spice in curry is turmeric. A major component of turmeric is curcumin.

“Curcumin has been around for a while. It is an FDA-Approved drug for cancer. A friend of mine in Los Angeles, Greg Cole, found that if you give curcumin to very similar mice to what this study’s author has been using, they get they get a little better, the (Alzheimer’s) plaques go away.

“The problem with curcumin is that it is not a great drug, in the sense that it gets degraded very rapidly. It’s availability is quite low in the bloodstream and the brain.

“We decided to make a better version of this. We did a lot of medicinal chemistry. We came up with J147.”

Lead study author Marguerite Prior, a research associate in Salk’s Cellular Neurobiology Laboratory, added,

“J147 is an exciting new compound because it really has strong potential to be an Alzheimer’s disease therapeutic by slowing disease progression and reversing memory deficits following short-term treatment.”

Because of its broad ability to protect nerve cells, the researchers believe that J147 may also be effective for treating other neurological disorders, such as Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS), as well as vascular dementia from stroke, although their study did not directly explore the drug’s efficacy as a therapy for those diseases.

The findings, published in the journal Alzheimer’s Research and Therapy, may pave the way to a new treatment for Alzheimer’s disease in humans.

Despite years of research, scientists are still seeking the first disease-modifying drugs for Alzheimer’s. Current FDA-approved medications, including Aricept®, Razadyne® and Exelon® (generic donepezil, galantamine and rivastigmine), offer only fleeting short-term benefits for Alzheimer’s patients, but they do nothing to slow the steady, irreversible decline of brain function that erases a person’s memory and ability to think clearly.

Professor Schubert and his colleagues bucked the trend within the pharmaceutical industry, which has focused on the biological pathways involved in the formation of amyloid plaques, the dense deposits of protein that characterize the disease. Instead, the Salk team used living neurons grown in laboratory dishes to test whether their new synthetic compounds, which are based upon natural products derived from plants, were effective at protecting brain cells against several pathologies associated with brain aging. From the test results of each chemical iteration of the lead compound, they were able to alter their chemical structures to make them much more potent. Although J147 appears to be safe in mice, the next step will require clinical trials to determine whether the compound will prove safe and effective in humans.

“Alzheimer’s disease research has traditionally focused on a single target, the amyloid pathway,” says Schubert, “but unfortunately drugs that have been developed through this pathway have not been successful in clinical trials. Our approach is based on the pathologies associated with old age-the greatest risk factor for Alzheimer’s and other neurodegenerative diseases-rather than only the specificities of the disease.”

J147
Salk scientists developed J147, a synthetic drug shown to improve memory and prevent brain damage in mice with Alzheimer’s disease.Images: Courtesy of the Salk Institute for Biological Studies

To test the efficacy of J147 in a much more rigorous preclinical Alzheimer’s model, the Salk team treated mice using a therapeutic strategy that they say more accurately reflects the human symptomatic stage of Alzheimer’s. Administered in the food of 20-month-old genetically engineered mice, at a stage when Alzheimer’s pathology is advanced, J147 rescued severe memory loss, reduced soluble levels of amyloid, and increased neurotrophic factors essential for memory, after only three months of treatment.

In a different experiment, the scientists tested J147 directly against Aricept (generic donepezil), the most widely prescribed Alzheimer’s drug, and found that it performed as well or better in several memory tests.

“In addition to yielding an exceptionally promising therapeutic, both the strategy of using mice with existing disease and the drug discovery process based upon aging are what make the study interesting and exciting,” says Schubert, “because it more closely resembles what happens in humans, who have advanced pathology when diagnosis occurs and treatment begins.” Most studies test drugs before pathology is present, which is preventive rather than therapeutic and may be the reason drugs don’t transfer from animal studies to humans.

Prior and her colleagues say that several cellular processes known to be associated with Alzheimer’s pathology are affected by J147, including an increase in a protein called brain-derived neurotrophic factor (BDNF), which protects neurons from toxic insults, helps new neurons grow and connect with other brain cells, and is involved in memory formation. Postmortem studies show lower than normal levels of BDNF in the brains of people with Alzheimer’s.

The Salk researchers say that J147, with its memory enhancing and neuroprotective properties, along with its safety and availability as an oral medication, would make an “ideal candidate” for Alzheimer’s disease clinical trials. They are currently seeking funding for such a trial.

MORE INFORMATION:
Other researchers on the study were Richard Dargusch, Jennifer L. Ehren and Chandra Chiruta, of the Salk Institute.The work was supported by the Alzheimer’s Drug Discovery Foundation, the Bundy Foundation, the Fritz Burns Foundation, the George E. Hewitt Foundation, the Alzheimer’s Association, and the National Institutes of Health.
 Protein Delivery Reagent Assists Neurodegeneration Research

http://www.biosciencetechnology.com/product-releases/2015/11/protein-delivery-reagent-assists-neurodegeneration-research
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AMSBIO announces that Belgian researchers have cited use of BioPORTER Protein Delivery Reagent to introduce Tau seeds into HEK293 cells. BioPORTER Protein Delivery Reagent is a unique lipid formulation that allows direct translocation of proteins into living cells.

Neurodegenerative tauopathies, including Alzheimer disease and frontotemporal dementias, are characterized by neurofibrillary tangles (NFT) composed of intracellular hyperphosphorylated Tau aggregates. Predominantly expressed in neurons, Tau is a microtubule (MT)-binding protein that stabilizes and promotes the assembly of MTs, and the Tau-MT interactions are negatively regulated by phosphorylation of Tau. A naturally unfolded soluble protein under normal conditions, Tau acquires highly ordered ß-pleated sheet structures as it assembles into insoluble hyperphosphorylated paired helical filaments as well as less frequent straight filaments that constitute NFTs in Alzheimer disease and related tauopathies. Significant correlation of total NFT burden with cognitive decline has been observed in Alzheimer disease patients.

In the Belgian research prion-like seeding and propagation of Tau-pathology was demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative Tauopathies. The researchers analyzed the repercussions of prion-like spreading of Tau-pathology via neuronal connections on neuronal network function in TauP301S transgenic mice.

BioPORTER Protein Delivery Reagent provided the researchers with a quick and easy method to study protein function without the need for cloning and DNA transfection. The  reagent lipid captures proteins and transports them inside the target cells. The delivered proteins retain their structure and function while leaving the transduced cells unharmed. The reagent is especially useful when studying protein function in cells that are difficult to transfect using traditional DNA transfection reagents. http://www.amsbio.com/BioPORTER-protein-delivery-transfectiom-reagent.aspx

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Brain-derived neurotrophic factor (BDNF)
By 26 Jun, 2010 Neurotrophic Factors

Neurotrophic factors are a family of proteins that are responsible for the growth and survival of nerve cells during development, and for the maintenance of adult nerve cells. Animal studies and test tube (in vitro Latin phrase for ‘in glass’; in a test tube or other artificial environment, as opposed to inside a living organism.”>in vitro)models

Organisms that scientists use to reproduce features of a disease of interest in an organism and then study it. For example, inserting the gene for HD into a mouse means that it will produce the altered HD protein in the brain. This creates an HD mouse model. The consistent use of these models allows researchers to test ideas about biology in a reproducible way, without the expense and ethical problems of performing these tests in humans.”>models have shown that certain neurotrophic factors are capable of making damaged nerve cells regenerate. Because of this capability, these factors represent exciting possibilities for reversing a number of devastating brain disorders, including Alzheimer’s disease

A neurodegenerative disease that causes progressive memory loss and severe dementia in advanced cases. Alzheimer’s disease is associated with certain abnormalities in brain tissue, involving a particular protein, beta-amyloid.”>Alzheimer’s disease, Parkinson’s disease

A neurodegenerative disorder that primarily affects one’s ability to perform smooth movements. The disease is associated with a loss of dopamine-producing nerve cells in the substantia nigra region of the brain.”>Parkinson’s disease, Lou Gehrig’s disease, and Huntington’s disease

A hereditary neurological disorder characterized by movement, cognitive, and psychiatric symptoms.”>Huntington’s Disease (HD). (For more information on how HD relates to Alzheimer’s and Parkinson’s, click here.) Currently, scientists are looking for ways to harness neurotrophic factors and somehow induce the damaged nerve cells to regenerate in order to improve the symptoms

Changes in the body or its functions, experienced by the patient and indicative of disease.”>symptoms of people with neurological having to do with nerve cells and/or the nervous system, particularly the brain”>neurological disorders.

One neurotrophic factor is a protein in the nervous system that promotes the growth of nerve cells.”>neurotrophic factor that is particularly relevant to HD is brain-derived neurotrophic factor (BDNF)

A protein that causes certain types of nerve cells to survive and grow. BDNF is primarily located in the central nervous system, where it acts on cells in the brain and the eye. In the peripheral nervous system, BDNF promotes the growth of sensory and motor neurons.”>Brain-derived neurotrophic factor (BDNF)

.BDNF

An abbreviation of brain-derived neurotrophic factor, which is a protein that causes certain types of nerve cells to survive and grow. BDNF is primarily located in the central nervous system, where it acts on cells in the brain and the eye. In the peripheral nervous system, BDNF promotes the growth of sensory and motor neurons.”>BDNF levels are decreased in the brains of HD patients, which might be partly responsible for the degenerative when a part of the body stops working well, and begins to decline in function”>degenerative processes of HD. Researchers have recently discovered a link between BDNF An abbreviation of brain-derived neurotrophic factor, which is a protein that causes certain types of nerve cells to survive and grow. BDNF is primarily located in the central nervous system, where it acts on cells in the brain and the eye. In the peripheral nervous system, BDNF promotes the growth of sensory and motor neurons.”>BDNF , mutant huntingtin

The altered form of the huntingtin protein caused by having the HD gene.”>mutant huntingtin , and excitotoxicity

Excessive stimulation of a nerve cell by a neurotransmitter, which poisons the nerve cell and degrades it.”>excitotoxicity, a process by which brain cells die after stimulation. The mutant huntingtin protein A key protein in Huntington’s disease. It exists in all humans but has a chemically different form in people with HD. Please note that although Huntingt<strong>o</strong>n’s disease is spelled with an o, the correct spelling of the protein involved is huntingt<strong>i</strong>n with an i.”>huntingtin protein invariably leads to the death of nerve cells in the striatum part of the brain that is involved in controlling movement. It is made up of the caudate and the putamen. Also referred to as the corpus striatum.”>striatum, the region of the brain needed for movements; however, how mutant huntingtin the altered form of the huntingtin protein caused by having the HD gene.”>mutant huntingtin does this damage is unclear. One possibility is that mutant huntingtin

The altered form of the huntingtin protein caused by having the HD gene.”>mutant huntingtin lowers levels of BDNF

An abbreviation of brain-derived neurotrophic factor, which is a protein that causes certain types of nerve cells to survive and grow. BDNF is primarily located in the central nervous system, where it acts on cells in the brain and the eye. In the peripheral nervous system, BDNF promotes the growth of sensory and motor neurons.”>BDNF, making nerve cells more susceptible to injury and death. Therefore, therapeutic approaches aimed at increasing BDNF

An abbreviation of brain-derived neurotrophic factor, which is a protein that causes certain types of nerve cells to survive and grow. BDNF is primarily located in the central nervous system, where it acts on cells in the brain and the eye. In the peripheral nervous system, BDNF promotes the growth of sensory and motor neurons.”>BDNF production may be able to counteract the effects ofmutant huntingtin

The altered form of the huntingtin protein caused by having the HD gene.”>mutant huntingtin and prevent a significant amount of the neurodegeneration

The deterioration or loss of function of nerve cells. Neurodegenerative diseases include HD, Alzheimer’s, Parkinson’s and many more. <em>Adj.</em>neurodegenerative.”>neurodegeneration that would otherwise occur in HD. (For more information on huntingtin protein

A key protein in Huntington’s disease. It exists in all humans but has a chemically different form in people with HD. Please note that although Huntingt<strong>o</strong>n’s disease is spelled with an o, the correct spelling of the protein involved is huntingt<strong>i</strong>n with an i.”>huntingtin protein

, click here.)

http://ghr.nlm.nih.gov/gene/BDNF

What is the official name of the BDNF gene?

The official name of this gene is “brain-derived neurotrophic factor.”

BDNF is the gene’s official symbol. The BDNF gene is also known by other names, listed below.

Read more about gene names and symbols on the About page.

What is the normal function of the BDNF gene?

The BDNF gene provides instructions for making a protein found in the brain and spinal cord called brain-derived neurotrophic factor. This protein promotes the survival of nerve cells (neurons) by playing a role in the growth, maturation (differentiation), and maintenance of these cells. In the brain, the BDNF protein is active at the connections between nerve cells (synapses), where cell-to-cell communication occurs. The synapses can change and adapt over time in response to experience, a characteristic called synaptic plasticity. The BDNF protein helps regulate synaptic plasticity, which is important for learning and memory.

The BDNF protein is found in regions of the brain that control eating, drinking, and body weight; the protein likely contributes to the management of these functions.

Does the BDNF gene share characteristics with other genes?

The BDNF gene belongs to a family of genes called endogenous ligands (endogenous ligands).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? in the Handbook.

Brain-derived Neurotrophic Factor      

DEVIN K. BINDERa,* and HELEN E. SCHARFMANb

Growth Factors. 2004 Sep; 22(3): 123–131.     doi:  10.1080/08977190410001723308
Nerve growth factor (NGF) was discovered in the early 1950s due to its trophic (survival- and growth-promoting) effects on sensory and sympathetic neurons (Levi-Montalcini and Hamburger, 1951), In 1982, brain-derived neurotrophic factor (BDNF), the second member of the “neurotrophic” family of neurotrophic factors, was shown to promote survival of a subpopulation of dorsal root ganglion neurons, and subsequently purified from pig brain (Barde et al., 1982). Since then, other members of the neurotrophin family such as neurotrophin-3 (NT-3) (Maisonpierre et al., 1990) and neurotrophin-4/5 (NT-4/5) (Hallbook et al., 1991; Ipet al., 1992) have been described, each with a distinct profile of trophic effects on subpopulations of neurons in the peripheral and central nervous systems.

The BDNF gene (in humans mapped to chromosome 11p) has four 5′ exons (exons I-IV) that are associated with distinct promoters, and one 3′ exon (exon V) that encodes the mature BDNF protein (Metsis et al., 1993; Timmusk et al., 1993). Eight distinct mRNAs are transcribed, with transcripts containing exons I-III expressed predominantly in brain and exon IV found in lung and heart (Timmusk et al., 1993).

BDNF shares about 50% amino acid identity with NGF, NT-3 and NT-4/5. Each neurotrophin consists of a noncovalently-1 linked homodimer and contains (1) a signal peptide following the initiation codon; and (2) a pro-region containing an N-linked glycosylation site. Initially produced as proneurotrophins, prohormone convertases such as furin cleave the proneurotrophins (M.W. ~30kDa) to the mature neurotrophin (M.W. ~14kDa) (Chao and Bothwell, 2002). Proneurotrophins have altered binding characteristics and distinct biologic activity in comparison with mature neurotrophins (Lee et al., 2001a,b). Neurotrophins also share a distinctive three-dimensional structure containing two pairs of antiparallel β-strands and cysteine residues in a cystine knot motif.

Each neurotrophin binds one or more of the tropomyosin-related kinase (trk) receptors, members of the family of receptor tyrosine kinases (Patapoutian and Reichardt, 2001). Ligand-induced receptor dimerization results in kinase activation; subsequent receptor autophosphorylation on multiple tyrosine residues creates specific binding sites for intracellular target proteins, which bind to the activated receptor via SH2 domains (Barbacid, 1994; Patapoutian and Reichardt, 2001). These include PLC-γ1 (phospholipase C), p85 (the noncatalytic subunit of PI-3 kinase) and Shc (SH2-containing sequence); activation of these target proteins can then lead to a variety of intracellular signalling cascades such as the Ras-MAP (mitogen-activated protein) kinase cascade and phosphorylation of cyclic AMP-response element binding protein (CREB) (Patapoutian and Reichardt, 2001; Segal, 2003).

TrkA binds NGF (with low-affinity binding by NT-3 in some systems); trkB binds BDNF and NT-4/5 with lower-affinity binding by NT-3; and trkC binds NT-3 (Barbacid, 1994). Trk receptors exist in both a full-length (trkB.FL) form as well as truncated (trkB.T1. trkB.T2) forms lacking the kinase domain (Eide et al., 1996; Fryer et al., 1997). Although most functions attributed to BDNF are associated with full-length trkB, several roles have been suggested for truncated receptors, including growth and development (Fryer et al., 1997; Yacoubian and Lo, 2000; Luikart et al., 2003) and negative modulation of trkB receptor expression and function (Eide et al., 1996; Haapasalo et al., 2001; Haapasalo et al., 2002). Expression of truncated trk receptors on astrocytes is upregulated following injury (Frisen et al.,1993) and may modulate neuronal vulnerability (Saarelainen et al., 2000a,b) and sequestration of BDNF in astrocytes (Biffo et al., 1995;Roback et al., 1995; Alderson et al., 2000). Recent studies have shown that BDNF activates glial calcium signalling by truncated trk receptors (Climent et al., 2000: Rose et al., 2003).

In addition, all of the neurotrophins bind to the p75 receptor, designated p75NTR. p75NTR, related to proteins of the tumor necrosis factor (TNFR) superfamily, has a glycosylated extracellular region involved in ligand binding, a transmembrane region, and a short cytoplasmic sequence lacking intrinsic catalytic activity (Chao and Hempstead, 1995; Dechant and Barde, 2002). Neurotrophin binding to p75NTR is linked to several intracellular signal transduction pathways, including nuclear factor-κB (NF-κB), Jun kinase and sphingo-myelin hydrolysis (Dechant and Barde, 2002). P75NTR signalling mediates biologic actions distinct from those of the trk receptors, notably the initiation of programmed cell death (apoptosis) (Casaccia-Bonnefil et al., 1996; Frade et al., 1996; Roux et al., 1999; Dechant and Barde, 2002). It has also been suggested that p75 may serve to determine neurotrophin binding specificity (Esposito et al., 2001; Lee et al., 2001a,b;Zaccaro et al., 2001).

BDNF GENE REGULATION

A multitude of stimuli have been described that alter BDNF gene expression in both physiologic and pathologic states (Lindholm et al., 1994). For example, light stimulation increases BDNF mRNA in visual cortex (Castrén et al., 1992), osmotic stimulation increases BDNF mRNA in the hypothalamus (Castrén et al., 1995; Dias et al., 2003), and whisker stimulation increases BDNF mRNA expression in somatosensory barrel cortex (Rocamora et al., 1996). Electrical stimuli that induce long-term potentiation (LTP) in the hippocampus, a cellular model of learning and memory, increase BDNF and NGF expression (Patterson et al., 1992; Castrén et al., 1993; Bramham et al., 1996). Even physical exercise has been shown to increase NGF and BDNF expression in hippocampus (Neeper et al., 1995). Interestingly, BDNF levels vary across the estrous cycle, which correlate with its effects on neural excitability (Scharfman et al., 2003).

Distinct BDNF 5′ exons are differentially regulated by stimuli such as neural activity. For example, exons I-III, but not exon IV, increase after kainic acid-induced seizures (Timmusk et al., 1993) or other stimuli that increase activity (Lauterborn et al., 1996; Tao et al., 2002). Protein synthesis is required for the effects of activity on exons I and II, but not III and IV, raising the possibility that the latter act as immediate early genes (Lauterborn et al., 1996; Castrén et al., 1998). The transcription factor CaRF activates transcription of exon III under the control of a calcium response element. CaRE1 (Tao et al., 2002). CREB, which can be stimulated by diverse stimuli ranging from activity to chronic antidepressant treatment (Nibuya et al., 1995,1996; Shieh et al., 1998; Tao et al., 1998; Shieh and Ghosh, 1999), also modulates exon III transcription. Recent evidence also indicates that neural activity triggers calcium-dependent phosphorylation and release of methyl-CpG binding protein 2 (MeCP2) from BDNF promoter III to derepress transcription (Chen et al., 2003).

LOCALIZATION, TRANSPORT AND RELEASE

BDNF and trkB mRNA have a widespread distribution in the central nervous system (Merlio et al., 1993;Conner et al., 1997). BDNF and trkB protein immunoreactivity is also widespread (Conner et al., 1997; Yanet al., 1997a,b; Drake et al., 1999), Like BDNF mRNA, constitutive BDNF protein expression is particularly high in the hippocampus, where the mossy fibre axons of dentate granule cells display BDNF immunoreactivity (Conner et al., 1997).

Unlike the classical target-derived trophic factor model in which neurotrophins—such as NGF—are retrogradely transported, there is now abundant evidence that BDNF is also anterogradely transported in brain. First, BDNF protein is localized to nerve terminals (Conner et al., 1997), and pathway transection or axonal transport inhibition abrogates this terminal expression (Altar et al., 1997; Conner et al., 1997; Altar and DiStefano, 1998). Second, higher-resolution studies have shown that BDNF is associated with dense-core vesicles (Fawcett et al., 1997; Altar and DiStefano, 1998), which are the primary site for neuropeptide storage and release from nerve terminals. Third, further functional studies have supported the anterograde transport hypothesis (Fawcett et al., 1998, 2000). Fourth, pro-BDNF is shuttled from the trans-Golgi network into secretory granules, where it is cleaved by prohormone convertase 1 (PC1) (Farhadi et al., 2000).

In addition, emerging evidence suggests that both BDNF and trk receptors may undergo regulated intracellular transport. For example, seizures lead to redistribution of BDNF mRNA from hippocampal CA3 cell bodies to their apical dendrites (Bregola et al., 2000; Simonato et al., 2002). Trk signalling is now thought to include retrograde transport of intact neurotrophin-trk complexes to the neuronal cell body (Miller and Kaplan, 2001; Ginty and Segal, 2002).

Recent evidence indicates that neurotrophins are released acutely following neuronal depolarization (Griesbeck et al., 1999; Mowla et al., 1999; Goggi et al., 2003). In fact, direct activity-dependent pre- to post-synaptic transneuronal transfer of BDNF has recently been demonstrated using fluorescently-labelled BDNF (Kohara et al., 2001). The released form of BDNF is thought to be proBDNF (Mowla et al., 2001), raising the possibility of postsecretory proteolytic processing by membrane-associated or extracellular proteases in the modulation of BDNF action (Lee et al., 2001a,b).

….. more

Experimental Drug Targeting Alzheimer’s Disease Shows Anti-aging Effects

http://www.biosciencetechnology.com/news/2015/11/experimental-drug-targeting-alzheimers-disease-shows-anti-aging-effects

Salk scientists Antonio Currais, David Schubert and team found a molecule that slows the clock on key aspects of aging in animals. Credit: Salk Institute

Salk scientists Antonio Currais, David Schubert and team found a molecule that slows the clock on key aspects of aging in animals. Credit: Salk Institute

Salk Institute researchers have found that an experimental drug candidate aimed at combating Alzheimer’s disease has a host of unexpected anti-aging effects in animals.

The Salk team expanded upon their previous development of a drug candidate, called J147, which takes a different tack by targeting Alzheimer’s major risk factor–old age. In the new work, the team showed that the drug candidate worked well in a mouse model of aging not typically used in Alzheimer’s research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain and other improved physiological features, as detailed November 12, 2015 in the journal Aging.

“Initially, the impetus was to test this drug in a novel animal model that was more similar to 99 percent of Alzheimer’s cases,” said Antonio Currais, the lead author and a member of Professor David Schubert’s Cellular Neurobiology Laboratory at Salk. “We did not predict we’d see this sort of anti-aging effect, but J147 made old mice look like they were young, based upon a number of physiological parameters.”

Alzheimer’s disease is a progressive brain disorder, recently ranked as the third leading cause of death in the United States and affecting more than five million Americans. It is also the most common cause of dementia in older adults, according to the National Institutes of Health.

“While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), none have proven effective in the clinic,” said Schubert, senior author of the study.

Several years ago, Schubert and his colleagues began to approach the treatment of the disease from a new angle. Rather than target amyloid, the lab decided to zero in on the major risk factor for the disease–old age. Using cell-based screens against old age-associated brain toxicities, they synthesized J147.

Previously, the team found that J147 could prevent and even reverse memory loss and Alzheimer’s pathology in mice that have a version of the inherited form of Alzheimer’s, the most commonly used mouse model. However, this form of the disease comprises only about 1 percent of Alzheimer’s cases. For everyone else, old age is the primary risk factor, said Schubert. The team wanted to explore the effects of the drug candidate on a breed of mice that age rapidly and experience a version of dementia that more closely resembles the age-related human disorder.

In this latest work, the researchers used a comprehensive set of assaid to measure the expression of all genes in the brain, as well as over 500 small molecules involved with metabolism in the brains and blood of three groups of the rapidly aging mice. The three groups of rapidly aging mice included one set that was young, one set that was old and one set that was old but fed J147 as they aged.

The old mice that received J147 performed better on memory and other tests for cognition and also displayed more robust motor movements. The mice treated with J147 also had fewer pathological signs of Alzheimer’s in their brains. Importantly, because of the large amount of data collected on the three groups of mice, it was possible to demonstrate that many aspects of gene expression and metabolism in the old mice fed J147 were very similar to those of the young animals. These included markers for increased energy metabolism, reduced brain inflammation and reduced levels of oxidized fatty acids in the brain.

Another notable effect was that J147 prevented the leakage of blood from the microvessels in the brains of old mice. “Damaged blood vessels are a common feature of aging in general, and in Alzheimer’s, it is frequently much worse,” said Currais.

Currais and Schubert note that while these studies represent a new and exciting approach to Alzheimer’s drug discovery and animal testing in the context of aging, the only way to demonstrate the clinical relevance of the work is to move J147 into human clinical trials for Alzheimer’s disease.

“If proven safe and effective for Alzheimer’s, the apparent anti-aging effect of J147 would be a welcome benefit,” adds Schubert. The team aims to begin human trials next year.

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Amyloid-Targeting Immunotherapy

Posted in Alzheimer's Disease, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Cognition, Curation, Disease Biology, Drug Toxicity, FDA Regulatory Affairs, Gene Regulation, Human aging, Immunotherapy, Monoclonal antibody therapy, Neurodegenerative Diseases, Pharmacotherapy and Cell Activity, tagged , , on November 11, 2015| Leave a Comment »

Amyloid-Targeting Immunotherapy

Curator: Larry H. Bernstein, MD, FCAP

Possible Reasons Found for Failure of Alzheimer’s Treatment

By Staff Editor

http://www.healthnewsdigest.com/news/Alzheimer_Issues_680/Possible-Reasons-Found-for-Failure-of-Alzheimer-s-Treatment.shtml

(HealthNewsDigest.com) – Agglutinated proteins in the brain, known as amyloid-β plaques, are a key characteristic of Alzheimer’s. One treatment option uses special antibodies to break down these plaques. This approach yielded good results in the animal model, but for reasons that are not yet clear, it has so far been unsuccessful in patient studies. Scientists at the Technical University of Munich (TUM) have now discovered one possible cause: they noticed that, in mice that received one antibody treatment, nerve cell disorders did not improve and were even exacerbated.

Immunotherapies with antibodies that target amyloid-β were long considered promising for treating Alzheimer’s. Experiments with animals showed that they reduced plaques and reversed memory loss. In clinical studies on patients, however, it has not yet been possible to confirm these results. A team of researchers working with Dr. Dr. Marc Aurel Busche, a scientist at the TUM hospital Klinikum rechts der Isar Klinik und Poliklinik für Psychiatrie und Psychotherapie and at the TUM Institute of Neuroscience, and Prof. Arthur Konnerth from the Institute of Neuroscience has now clarified one possible reason for this. The findings were published in Nature Neuroscience.

Immunotherapy Increases Number of Hyperactive Nerve Cells

The researchers used Alzheimer’s mice models for their study. These animals carry a transgene for the amyloid-β precursor protein, which, as in humans, leads to the formation of amyloid-β plaques in the brain and causes memory disorders. The scientists treated the animals with immunotherapy antibodies and then analyzed nerve cell activity using high-resolution two-photon microscopy. They found that, while the plaques disappeared, the number of abnormally hyperactive neurons rose sharply.

“Hyperactive neurons can no longer perform their normal functions and, after some time, wear themselves out. They then fall silent and, later, possibly die off,” says Busche, explaining the significance of their discovery. “This could explain why patients who received the immunotherapy experienced no real improvement in their condition despite the decrease in plaques,” he adds.

Released Oligomers Potential Reason for Hyperactivity

Even in young Alzheimer’s mice, when no plaques were yet detectable in the brain, the antibody treatment led to increased development of hyperactive nerve cells. “Looking at these findings, even using the examined immunotherapies at an early stage, before the plaques appear, would offer little chance of success. As the scientist explains, the treatment already exhibits these side effects here, too.

“We suspect that the mechanism is as follows: The antibodies used in treatment release increasing numbers of soluble oligomers. These are precursors of the plaques and have been considered problematic for some time now. This could cause the increase in hyperactivity,” says Busche.

The work was funded by an Advanced ERC grant to Prof. Arthur Konnerth, the EU FP7 program (Project Corticonic) and the Deutsche Forschungsgemeinschaft (IRTG 1373 and SFB870). Marc Aurel Busche was supported by the Hans und Klementia Langmatz Stiftung.

Publication
Marc Aurel Busche, Christine Grienberger, Aylin D. Keskin, Beomjong Song, Ulf Neumann, Matthias Staufenbiel, Hans Förstl and Arthur Konnerth, Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models, Nature Neuroscience, November 9, 2015.
DOI: 10.1038/nn.4163
http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4163.html

Amyloid-Targeting Immunotherapy Disrupts Neuronal Function

Some antibodies designed to eliminate the plaques prominent in Alzheimer’s disease can aggravate neuronal hyperactivity in mice.

By Karen Zusi | November 9, 2015  http://www.the-scientist.com//?articles.view/articleNo/44435/title/Amyloid-Targeting-Immunotherapy-Disrupts-Neuronal-Function/

http://www.the-scientist.com/images/News/November2015/10_alzheimerbrain_b.jpg

Removing built-up plaques of amyloid-β in the brain is a long-sought therapy for patients with Alzheimer’s disease, but for a variety of reasons, few treatments have succeeded in alleviating symptoms once they reach clinical trials. In a study published today (November 9) in Nature Neuroscience, an international team examined the effects of two amyloid-β antibodies on neuronal activity in a mouse model, finding that the antibodies in fact led to an increase in neuronal dysfunction.

Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models

Marc Aurel Busche, Christine Grienberger, Aylin D Keskin, Beomjong Song, Ulf Neumann, Matthias Staufenbiel, Hans Förstl & Arthur Konnerth
Nature Neuroscience (2015)    http://dx.doi.org:/10.1038/nn.4163

Among the most promising approaches for treating Alzheimer´s disease is immunotherapy with amyloid-β (Aβ)-targeting antibodies. Using in vivo two-photon imaging in mouse models, we found that two different antibodies to Aβ used for treatment were ineffective at repairing neuronal dysfunction and caused an increase in cortical hyperactivity. This unexpected finding provides a possible cellular explanation for the lack of cognitive improvement by immunotherapy in human studies.

Marc Busche, a psychiatrist at Technical University of Munich in Germany, and others had previously found that neuronal hyperactivity is common in mouse models of Alzheimer’s disease. The chronically rapid-firing neurons can interfere with normal brain function in mice. “There’s evidence from human fMRI [functional magnetic resonance imaging] studies that humans will show hyperactivation early in the disease, followed by hypoactivation later on,” Busche told The Scientist. “It’s an early stage of neuronal dysfunction that can later turn into neural silencing.”

To investigate whether certain antibodies would alleviate this Alzheimer’s disease-associated phenotype, Busche and his colleagues first turned to bapineuzumab—a human monoclonal antibody that initially showed promise in treating mice modeling Alzheimer’s disease, but failed in human clinical trials. The dominant hypothesis for bapineuzumab’s failure is that it was administered too late in the disease progression, said Busche. “But it’s still a hypothesis,” he added. “There’s no real explanation for why these antibodies failed.”

The team’s latest experimenters used mice with a genetic mutation that caused them to overexpress the human amyloid-β protein; these engineered mice also displayed neuronal hyperactivity. The researchers injected 3D6, the mouse version of bapineuzumab, into the engineered mice, as well as into wild-type mice that had normal expression levels of the mouse amyloid-β protein. The team observed the effects using two-photon calcium imaging in a blinded study.

As expected, 3D6 decreased the amount of amyloid-β plaques in the engineered mice, while the control mice displayed no reaction to the injected antibodies. However, the mice engineered to overexpress human amyloid-β showed increased neuronal hyperactivity in response to the antibody, regardless of what stage of plaque development they were in. Even mice too young to have developed plaques showed aggravated hyperactive neurons. The team observed the same phenomenon when it tested a second antibody, β1, which went through early stages of drug development but was never used in human clinical trials.

As expected, 3D6 decreased the amount of amyloid-β plaques in the engineered mice, while the control mice displayed no reaction to the injected antibodies. However, the mice engineered to overexpress human amyloid-β showed increased neuronal hyperactivity in response to the antibody, regardless of what stage of plaque development they were in. Even mice too young to have developed plaques showed aggravated hyperactive neurons. The team observed the same phenomenon when it tested a second antibody, β1, which went through early stages of drug development but was never used in human clinical trials.

The results surprised Busche. “When it turned out that the antibody group was worse than the control group, it was unbelievable. But we checked many times and there was no mistake,” he said. “We don’t see this effect in wild-type mice so it must be dependent on the interaction between the antibody and amyloid-β.”

Busche was quick to point out that the mouse model is not the same as a human Alzheimer’s patient. However, he said, “it gives a sense that we don’t understand the antibody’s action, and this might go on in the human brain as well.”

“I fully believe in their results, but I have some hesitation in saying that this result explains the failed clinical trials for amyloid-β immunotherapy,” said Cynthia Lemere, a neurologist and Alzheimer’s disease researcher at the Brigham and Women’s Hospital in Boston. “I think the major reason for clinical trials failing for immunotherapy is that up until now, they’ve been done in people with moderate-to-severe Alzheimer’s disease, and then mild-to-moderate. Now the studies are going further to include people with very early stages of clinical symptoms—and to my knowledge, they haven’t been stopped because patients are getting worse.”

Thomas Wisniewski, a cognitive neurologist at New York University, voiced a similar perspective. “I don’t think this is an explanation for why immunotherapy isn’t working—I think there are other more plausible reasons for that,” he said, citing clinical trials that treated patients during later stages of Alzheimer’s disease progression, as well as those that haven’t addressed tau-related pathologies, or didn’t target the key types of amyloid-β. “[The neuronal hyperactivity] is an interesting phenomenon to be studied,” he added, “but I think it’s a separate issue.”

M.A. Busche et al., “Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models,” Nature Neuroscience, doi:10.1038/nn.4163, 2015.

Tags

neurons, monoclonal antibodies, memory, clinical trials and Alzheimer’s Disease

Figure 1: Anti-Aβ antibody 3D6 reduces amyloid pathology but aggravates neuronal dysfunction.

Anti-A[beta] antibody 3D6 reduces amyloid pathology but aggravates neuronal dysfunction.

(a) Amyloid burden was markedly reduced in 3D6-treated (green) compared with isotype-treated control (black) PDAPP mice. Each dot represents an individual animal, the horizontal bar represents the mean and the error bars represent ±s.e…

http://www.nature.com/neuro/journal/vaop/ncurrent/carousel/nn.4163-F1.jpg

Figure 2: Worsening of neuronal dysfunction by anti-Aβ antibodies can occur independently of the effects on Aβ pathology.

Worsening of neuronal dysfunction by anti-A[beta] antibodies can occur independently of the effects on A[beta] pathology.

(a) Top, representative in vivo activity maps in WT (left) as well as isotype-treated (middle) and β1-treated (right) Tg2576 mice. Bottom, Ca2+ transients of neurons indicated above. The further aggravation of neuronal hyperactivity (mi…

http://www.nature.com/neuro/journal/vaop/ncurrent/carousel/nn.4163-F2.jpg

Anti-Aβ treatment aggravates abnormal brain activity in a mouse model of Alzheimer’s disease

Nature Neuroscience   Nov 10, 2015

http://www.natureasia.com/en/research/highlight/10316

Therapies that reduce deposits of amyloid-β (Aβ) in the brain are ineffective at repairing neuronal impairment in mice and actually increase it, finds a study published online in Nature Neuroscience. Aβ deposits aggregate into clumps in the brain which are a pathological hallmark of Alzheimer’s disease.

Expression of mutant human amyloid protein in animals results in deposits of Aβ plaques that induce abnormal increases in neuronal activity and impair the normal function of neuronal circuits.

Arthur Konnerth, Marc Busche and colleagues explored whether they could reverse these impairments by treating mice that overexpress the human mutant amyloid precursor protein with either of two different antibodies targeting Aβ (14 mice) or a control antibody (19 mice). They found that, although treatment with the Aβ targeting antibodies reduced the amount of plaques in the animals’ brains, it also increased the amount of hyperactive neurons.

This was true whether the treatment was given to older mice (14 treated, 19 control) or younger mice in which the accumulation of Aβ had yet to occur (10 treated, 13 control). The same therapies had no effect on neuronal activity in a group of normal mice (5 treated, 3 control), suggesting that the observed exacerbation in mutant mice is dependent on the presence of Aβ and cannot be explained by incidental effects of inflammation in response to the antibodies.

The authors note that, although other research has shown that anti-Aβ treatment can prevent the weakening of neuronal connections and memory impairments in animal models of Alzheimer’s disease, these benefits are not enough to repair neuronal dysfunction.

They suggest that their findings provide a cellular mechanism that may explain, in part, why treatments targeting Aβ in human clinical trials have failed to improve cognitive deficits. However, the authors point out that future studies are needed to determine whether the increase in abnormal neural activity seen in their animal models is related to the poor efficacy of Aβ therapy in patients.

 

ANAVEX™ 2-73

ANAVEX™ 2-73 is an orally available drug candidate developed to potentially modify Alzheimer’s disease rather than temporarily address its symptoms. It has a clean Phase 1 data profile and shows reversal of memory loss (anti-amnesic properties) and neuroprotection in several models of Alzheimer’s disease.

Successful Phase 1 Clinical Trial

A Phase 1 single ascending dose human clinical trial of ANAVEX 2-73 was successfully completed in healthy human volunteers. It was a randomized, placebo-controlled study. Healthy male volunteers aged 18 to 55 received single, ascending oral doses over the course of the trial. The trial objectives were to define the maximum tolerated dose, assess pharmacokinetics (PK), clinical and lab safety.

Results:

  • Dosing from 1-60 mg.
  • Maximum tolerated dose 55-60 mg; above the equivalent dose shown to have positive effects in mouse models of Alzheimer’s disease.
  • Well tolerated below the 55-60 mg dose with only mild adverse events in some volunteers.
  • Observed adverse events at doses above the maximum tolerated single dose included headache and dizziness, which were moderate in severity and reversible. These side effects are often seen with drugs that target central nervous system (CNS) conditions, including Alzheimer’s disease.
  • No significant changes in blood safety measurements.
  • No changes in ECG.
  • Favorable PK profile.
    • Rapid absorption into blood.
    • Dose proportional kinetics.

The trial was conducted in Germany by ABX-CRO in collaboration with the Technical University of Dresden. ABX-CRO and the Technical University of Dresden are well regarded for their experience with clinical trials and CNS compounds.

 

ANAVEX 2-73,

Clinical-stage biopharmaceutical company Anavex Life Sciences Corp. is working on an investigational oral treatment for Alzheimer’s disease called ANAVEX 2-73, with full PART A data and preliminary PART B data from its ongoing Phase 2a clinical trial to be presented during the Clinical Trials on Alzheimer’s Disease (CTAD) conference, November 5 and 7 in Barcelona, Spain.

The trial’s Principal Investigator, Stephen Macfarlane, who also serves as director and associate professor at Aged Psychiatry, Caulfield Hospital in Melbourne, Australia, will represent the company and host a late-breaking oral session entitled “New Exploratory Alzheimer’s Drug ANAVEX 2-73: Assessment of Safety and Cognitive Performance in a Phase 2a Study in mild-to-moderate Alzheimer’s Patients.” During the presentation, which will take place Saturday, November 7, at 9:45 a.m. CET, at the Gran Hotel Princesa Sofia, in Barcelona, Macfarlane will focus on the the multicenter Phase 2a clinical trial of ANAVEX 2-73. The study includes two separate phases and includes 32 mild-to-moderate Alzheimer’s patients. While PART A is a simple randomized, open-label, two-period, cross-over, adaptive trial of up to 36 days, PART B is an open-label extension trial for an additional 52 weeks.

The research intends to assess the maximum dose of treatment tolerated by patients, and to explore cognitive efficacy using mini-mental state examination score (MMSE), dose response, bioavailability, Cogstate and electroencephalographic (EEG) activity, including event-related potentials (EEG/ERP), as well as the preformance of ANAVEX 2-73 as an add-on therapy to donepezil (Aricept).

ANAVEX 2-73 is Anavex’s lead investigational treatment for Alzheimer’s disease, in line with the company’s goal of finding effective therapies for Alzheimer’s disease, other central nervous system (CNS) diseases, pain, and various types of cancer. The novel drug targets sigma-1 and muscarinic receptors, which are thought to decrease the amount of protein misfolding, beta amyloid tau and inflammation through upstream actions.

Last November, the biopharmaceutical company presented encouraging results from their phase 1 clinical trial for Anavex 2-73, during the CNS Summit 2014 in Boca Raton, Florida. The phase 1 study demonstrated that the treatment is safe and well tolerated, suggesting a favorable pharmacokinetics profile. During the randomized, double-blind, placebo-controlled study no severe adverse events were registered, while the adverse events reported included moderate and reversible headache and dizziness, which are common symptoms associated with drugs that target central nervous system (CNS) conditions, such as Alzheimer’s.

New Exploratory Alzheimer’s Drug ANAVEX 2-73: Assessment of Safety and Cognitive Performance in a Phase 2a Study in mild-to-moderate Alzheimer’s Patients

Steve Macfarlane, MD1 , Paul Maruff, PhD2 , Marco Cecchi, PhD3 , Dennis Moore, PhD3 , Anastasios Zografidis, PhD4 , Christopher Missling, PhD4 (1)

Caulfield Hospital, Melbourne, Australia (2), Cogstate, Melbourne, Australia (3), Neuronetrix, KY, USA (4), Anavex Life Sciences, Corp., New York, NY, USA

Background: Despite major efforts aimed at finding a treatment for Alzheimer’s disease (AD), progress in developing compounds that can relieve cognitive deficits associated with the disease has been slow. ANAVEX 2-73 is a sigma-1 and muscarinic receptor agonist that in preclinical studies has shown memory-preserving and neuroprotective effects. In our ongoing phase 2a clinical study we are assessing ANAVEX 2-73 safety in subjects with mild-to-moderated AD, and measuring drug effects on MMSE, EEG and Event Related Potentials (ERP) cognitive measures, and Cogstate test batteries to optimize dosing.

Methods: Thirty-two subjects that meet NINCDS-ADRDA criteria for probable AD are being recruited at up to seven clinical sites in Melbourne, Australia. Subjects are between 55 and 85 years of age, and have an MMSE of 16 to 28. In PART A of the study, participants are administered ANAVEX 2-73 orally and IV in an open-label, 2-period, cross-over trial with adaptive study design lasting up to 36 days for each participant. In PART B of the study, all participants are administered ANAVEX 2-73 daily orally. MMSE, EEG/ERP (P300) and Cogstate tests are performed at baseline and subsequently at weeks 12, 26, 38 and 52 of the PART B open label extension.

Results: The primary outcome of the study is safety, and ANAVEX 2-73 was well tolerated. In the secondary outcome endpoints preliminary analysis of data from subjects shows an average improvement of the MMSE score at week 5. A majority of all patients tested so far improved their respective MMSE score. The average EEG/ERP (P300 amplitude) signal also improved and also the average Cogstate test improved across the test batteries.

Conclusions: Data collected so far indicate that ANAVEX 2-73 is safe and well tolerated. Interim results also show improved cognitive performance after drug administration in subjects with mild-to-moderate AD. The current results seem to justify a prospective comparison with current standard of care in a larger clinical trial study. A more complete set of results will be available at the time of the conference.

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Notable Awards – 2015

Posted in Alzheimer's Disease, Etiology, Innovations, Neuroscience, tagged , , , on November 9, 2015| Leave a Comment »

Notable Awards – 2015

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Breakthrough Prizes Give Top Scientists the Rock Star Treatment

By THE NEW YORK TIMES NOV. 8, 2015   Life Sciences
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http://www.nytimes.com/interactive/2015/11/06/science/breakthrough-prize-winners-2016.html

The richest awards in science were handed out Sunday night when theBreakthrough Prize organization presented a total of $21.9 million to physicists, mathematicians, life scientists and one talented high school student. The awards take the form of seven $3 million awards, one of which was split among roughly 1,300 physicists; $500,000 split among eight early-career researchers; and $400,000 to a high school student for creating a video communicating a scientific concept.

The Breakthrough Prizes were founded by Sergey Brin of Google; Anne Wojcicki of 23andme; Jack Ma of Alibaba and his wife, Cathy Zhang; Yuri Milner, an Internet entrepreneur, and his wife, Julia Milner; and Mark Zuckerberg of Facebook and his wife, Priscilla Chan.

“By challenging conventional thinking and expanding knowledge over the long term, scientists can solve the biggest problems of our time,” Mr. Zuckerberg said in a statement. “The Breakthrough Prize honors achievements in science and math so we can encourage more pioneering research and celebrate scientists as the heroes they truly are.”

Left, Karl Deisseroth, Stanford School of Medicine; Edward S. Boyden of the McGovern Institute for Brain Research at M.I.T.Left, Winni Wintermeyer for The New York Times; Dominick Reuter/M.I.T. News

http://i1.nyt.com/images/2015/11/08/science/08breakthrough_comp_1/08breakthrough_comp_1-tmagArticle.jpg

Karl Deisseroth and Edward S. Boyden
Optogenetics

Karl Deisseroth, a professor at Stanford University and a Howard Hughes Medical Institute investigator, and Edward S. Boyden, a professor at the Massachusetts Institute of Technology, each received $3 million for their roles in the development of optogenetics, a technique that allows scientists to use light to turn neurons and groups of neurons on and off.

The technique is transforming the study of the brain because it allows scientists to test ideas about how the brain works. It has already been used to turn a kind of aggression on and off in flies, and thirst on and off in mice, pinpointing the brain cells involved.

The technique is universally praised, but the question of who will be recognized for its development is an issue for any prize committee. Dr. Boyden, Dr. Deisseroth and three other scientists published a paper in 2005that is recognized as a breakthrough. They demonstrated how to reliably control mammalian neurons with light, making widespread use of the technique inevitable.

Their paper built on earlier work, as much of science does. Opsins, light-sensitive chemicals that are crucial to optogenetics, have been studied since the 1970s. And the fact that optogenetics could be done was demonstrated in 2002.

In 2013, the European Brain Prize recognized six scientists for work on optogenetics, including Dr. Boyden and Dr. Deisseroth.

JAMES GORMAN

 

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John Hardy
Alzheimer’s research

Alzheimer’s disease was a complete mystery in the late 1980s. In autopsies, pathologists could see the ravages left in patients’ brains, but how and why did the process start? There were rare families in which the disease seemed to be inherited, though, and perhaps there was a gene mutation that might provide a clue to what goes awry. The problem was finding those families.

In the late 1980s, a woman who lived in Nottingham, England, contacted John Hardy at University College London and asked if he and his team wanted to study her family. Her father was one of 10 siblings, five of whom had developed Alzheimer’s disease, and she could trace the disease back for three generations. Their investigation led to the discovery of a gene mutation that, if inherited, always caused the disease. The gene was presenilin, and its protein was the amyloid precursor protein, or APP. Every person in that family who inherited the gene overproduced amyloid and got the disease. For the first time, scientists had a clue to what starts the horrendous destruction of brain cells in Alzheimer’s disease. And for the first time, by putting that gene mutation in mice, they could study Alzheimer’s in a lab animal, look for drugs to block the gene’s effects and finally use the tools of science to look for a cure.

GINA KOLATA

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Helen Hobbs
Cholesterol research

Helen Hobbs, a professor at the University of Texas Southwestern Medical Center and a Howard Hughes Medical Institute investigator, and her colleague Jonathan Cohen were intrigued when they read a short paper describing a French family with stunningly high levels of LDL cholesterol, the dangerous kind, and early deaths from heart attacks and strokes. The family members turned out to have a mutation in a gene, PCSK9, whose function was unknown. Dr. Hobbs and Dr. Cohen began to wonder: If too much PCSK9 caused heart disease, would people who made too little be protected? They scrutinized genetic data from a federal study and found that about 2.5 percent of blacks had a mutation that destroyed one copy of the gene; 3.2 percent of whites had a mutation that hobbled a copy of the gene but did not destroy it. In both cases, less PCSK9 was made and LDL levels were low. The people with the mutations seemed almost immune to heart disease, even if they had other risk factors like high blood pressure, smoking or diabetes.

What would happen if someone had both copies of PCSK9 destroyed? Dr. Hobbs found one young woman, an aerobics instructor, without PCSK9. She was healthy and fertile even though her LDL level was 14, lower than seemed possible (the average is 100). That discovery led to a race among drug companies to make cholesterol-lowering drugs that mimicked the effects of the PCSK9 mutations. The result is drugs that can make LDL levels plunge to the 30s, the 20s, even the teens. The first two such PCSK9 inhibitors were approved this year for people with high cholesterol levels who cannot get them down with statins and are at high risk of heart disease.

GINA KOLATA

 

TED Prize Goes to Archaeologist Who Combats Looting With Satellite Technology
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http://www.nytimes.com/2015/11/09/arts/international/ted-grant-goes-to-archaeologist-who-combats-looting-with-satellite-technology.html

 

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Neural Networks in Alzheimer’s

Posted in Alzheimer's Disease, Cell Biology, Cerebrovascular and Neurodegenerative Diseases, Clinical & Translational, Clinical Diagnostics, Clinical Genomics, Curation, Disease Biology, Etiology, Gene Regulation, Innovations, Neurodegenerative Diseases, Neurological Diseases, Neuroscience, Pharmaceutical Analytics, Population Health Management, Proteins, Proteomics, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, tagged , , , , on November 5, 2015| Leave a Comment »

Neural Networks in Alzheimer’s

Larry H. Bernstein, MD, FCAP, Curator

LPBI

SfN 2015 Recap: The Role of Synapses, Neural Networks in Alzheimer’s

Stephanie Guzowski, Editor

http://www.dddmag.com/articles/2015/11/sfn-2015-recap-role-synapses-neural-networks-alzheimers

http://www.dddmag.com/sites/dddmag.com/files/perineuronal%20nets_SfN.jpg

Perineuronal nets, shown in green, in three regions of the mouse brain. Credit: S.F. Palida et al.

Cognition and behavior rely on communication between individual neurons and extensive interactions between neural networks. But when synaptic dysfunction occurs, the results can be dire, leading to neurodegenerative symptoms in Alzheimer’s disease.

“The brain is the seed of our personal identity,” said Valina Dawson, Ph.D., director of neurogeneration and stem cell programs at Johns Hopkins University in Baltimore, Maryland. “It allows us to interact with our world but when things go wrong in the brain, it’s disastrous for the individual as well as the family.

“Our ability to treat these diseases is limited at the moment. We need new insight into what goes wrong.”

A lesser-known protein

Researchers, for years, have targeted amyloid beta (Aβ) in attempts to halt the progression of Alzheimer’s disease, and have recently, shown increased interest in the protein, tau.

But Paula Pousinha, Ph.D., at the French National Centre for Scientific Research, has focused her research on a lesser-known protein fragment: amyloid precursor protein intracellular domain (AICD). AICD is a fragment of amyloid precursor protein (APP), which is formed at the same time as Aβ in the brain. New evidence suggests that in addition to Aβ, AICD also disrupts communication between neurons during the progression of Alzheimer’s disease. Pousinha presented thesepublished findings at this year’s Society for Neuroscience (SfN) conference, which took place from October 17 to 21 in Chicago.

“Although AICD has been known for more than 10 years, it has been poorly studied,” said Pousinha.

Pousinha’s research team demonstrated that overexpressing AICD levels with AAV vector in rats’ brains “perturbs neuronal communication in the hippocampus,” a key structure necessary in forming memories and an area earliest affected in Alzheimer’s disease.

“In normal animals, if we apply to these neurons a high-frequency stimulation, afterward the neurons are stronger,” said Pousinha. “Neurons where we overexpressed AICD failed to have this potentization.”

Pousinha doesn’t negate the importance of Aβ in the development of neurodegenerative diseases. “Our study doesn’t exclude the pathological effects of Aβ,” she said. “We believe that Alzheimer’s disease is much more complex and has more than one candidate that has implications.

“It’s very important for the scientific community to understand the role of all these APP fragments of neuroinflammation — different pieces of the puzzle of how we can stop the disease progression.”

How do memories persist in the brain long term?

New research, also presented at this year’s SfN, has implications for understanding memory to develop treatments for Alzheimer’s disease and dementias. Sakina Palida, a graduate student at the University of California, San Diego found that localized modifications in the perineuronal net (PNN) at synapses could be a mechanism by which information is stably encoded and preserved in the brain over time.

“We still don’t understand how we stably encode and store memories in our brains for up to our entire lifetimes,” said Palida. The prevailing idea on how memories are maintained over time generally focus on postsynaptic proteins, said Palida. “But the problem with looking at intracellular synaptic proteins is that the majority turn over rapidly, of hours to at most a few days. So they’re very unstable.”

So, Palida and her team identified PNN as an ideal substrate for long-term memory. “Kind of like how you carve into stone — stone is a stable substrate — you retain the information regardless of what comes and goes over it.” They demonstrated that individual PNN proteins are highly stable, and that the PNN is locally degraded when synapses are strengthened.

And the team also demonstrated that mice lacking enzymes that degrade the PNN have deficient long-term, but not short-term, memory. “Which is a really exciting new result,” said Palida.

To track the PNN in live animals, Palida and her team fused a fluorescent protein to a small link protein in the PNN to allow tracking of PNN dynamics in real time. They also monitored PNN degradation in live cells after stimulating neurons with brain-derived neurotrophic factor (BDNF), a chemical secreted in the nervous system to enhance signaling — and observed localized degradation of the PNN at some newly formed synapses.

Crtl 1-Venus. Fusion of a fluorescent protein to small link proteins in the PNN allows tracking of PNN dynamics over time. Credit: S.F. Palida et al. Crtl1-Venus Neurons. Tracking PNN dynamics in live cells, in mouse brain tissue. Credit: S.F. Palida et al.

What’s next? “We’re currently making transgenic animals to express this protein, which would allow us to monitor PNN dynamics simultaneously with synaptic dynamics in a live animal brain, and really investigate this hypothesis further,” said Palida.

Increased APP intracellular domain (AICD) production perturbs synaptic signal integration via increased NMDAR function

*Paula A Pousinha1PubmedElisabeth Raymond1PubmedXavier Mouska1PubmedMichael Willem2PubmedHélène Marie1Pubmed

1660 Route de Lucioles, CNRS IPMC UMR 7275, Valbonne, France; 2Ludwig-Maximilians-University Munich, Munich, Germany

Alzheimer’s disease (AD) is a neurodegenerative disease that begins as mild short-term memory deficits and culminates in total loss of cognition and executive functions. The main culprit of the disease, resulting from Amyloid-Precursor Protein (APP) processing, has been thought to be amyloid-b peptide (Ab). However, despite the genetic and cell biological evidence that supports the amyloid cascade hypothesis, it is becoming clear that AD etiology is complex and that Ab alone is unable to account for all aspects of AD [Pimplikar et al. J Neurosci.30: 14946. 2010]. Gamma-secretase not only liberates Ab, but also its C-terminal intracellular counterpart called APP intracellular domain (AICD) [Passer. et al. JAlzheimers Dis.2: 289-301. 2000], which is known to also accumulate in AD patient’s brain [Ghosal et al. PNAS.106:18367. 2009], but surprisingly little is known about its functions in the hippocampus. To address this crucial issue, we increased AICD production in vivo in adult CA1 pyramidal neurons, mimicking the human pathological condition. Different ex-vivo electrophysiological and pharmacological approaches, including double- patch of neighbor neurons were used. We clearly demonstrate that in vivo AICD production increases synaptic NMDA receptor currents. This causes a frequency-dependent disruption of synaptic signal integration, leading to impaired long-term potentiation, which we were able to rescue by different pharmacological approaches. Our results provide convincing and entirely novel evidence that increased in vivo production of AICD is enough, per se, to cause synaptic dysfunction in CA1 hippocampal neurons.

131.21P2X2R-FE65 interaction induces synaptic failure and neuronal dyshomeostasis after treatments with soluble oligomers of amyloid beta peptide

300.15Early synaptic deficits in Alzheimer’s disease involve neuronal adenosine A2A receptors

215.08Homeostatic coupling between surface trafficking and cleavage of amyloid precursor protein

280.11A novel mechanism for lowering Abeta

383.22Impact of intracellular soluble oligomers of amyloid-β peptide on glutamatergic synaptic transmission

Society for Neuroscience Annual Meeting Showcases Strides in Brain Research

10/23/2015 – Stephanie Guzowski, Editor

CHICAGO – Nearly 30,000 researchers from more than 80 countries gathered this week at the annual Society for Neuroscience (SfN) meeting, the world’s largest conference focused on scientific discovery related to the brain and nervous system.

The 45th annual SfN meeting at McCormick Place convention center showcased more than 15,000 scientific presentations on advances in technologies and new research about brain structure, disease and treatments, and 517 exhibitors, according to event organizers.

Presentations covered a wide variety of topics including new technologies to study the brain, the science behind addiction, potential treatments for spinal cord injuries, and the role of synapses in neurological conditions.

Of particular focus was the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the large collaborative quest to develop technologies for a dynamic view of the brain. In early October, the National Institutes of Health announced its second round of funding to support goals, bringing the NIH investment to $85 million in fiscal year 2015.

Toxic Tau Could be Key to Alzheimer’s Treatment

01/06/2015 – Stephanie Guzowski, Editor

http://www.dddmag.com/articles/2015/01/toxic-tau-could-be-key-alzheimers-treatment

http://www.dddmag.com/sites/dddmag.com/files/tangles_Alz2.jpg

“But now, we know that tau is not simply a bystander but also a player,” Li said. “Both proteins work together to damage cell functions as the disease unfolds.”

Targeting tau

In the healthy brain, tau protein helps with the building and functioning of neurons. But when tau malfunctions, it creates abnormal clumps of protein fibers—neurofibrillary tangles—which spread rapidly throughout the brain. This highly toxic and altered form of the brain protein tau is called “tau oligomer.”

“There’s growing evidence that tau oligomers, not tau protein in general, are responsible for the development of neurodegenerative diseases, like Alzheimer’s,” said Julia Gerson, a graduate student in neuroscience at the University of Texas Medical Branch.

In Gerson’s research, which she presented at this year’s Society for Neuroscience meeting in Washington, D.C., Gerson and her team injected tau oligomers from people with Alzheimer’s into the brains of healthy mice. Subsequent testing revealed that the mice had developed memory loss.

“When we inject mice with tau oligomers, we see that they spend the same amount of time exploring a familiar object as an unfamiliar object,” said Gerson. “So they’re incapable of remembering that they’ve already seen this familiar object.”

What’s more, the molecules had multiplied throughout the animals’ brains. “This suggests that tau oligomers may spread from the injection site to other unaffected regions,” said Gerson.

Future treatments

Understanding tau’s connection to Alzheimer’s could have implications for potential therapies. “If we can stop the spread of these toxic tau oligomers, we may be capable of either preventing, or reversing, symptoms,” said Gerson. Gerson’s lab is currently investigating antibodies, which specifically fight tau oligomers.

Click to Enlarge. Normal brain vs. Alzheimer’s brain (Credit: Garrondo)

Erik Roberson, M.D., Ph.D., at the University of Alabama at Birmingham, and colleagues looked at how boosting the function of a specific type of neurotransmitter receptor, the NMDA receptor, provided benefit to people with the second most common type of dementia: frontotemporal dementia (FTD), a disease in which people experience rapid and dramatic changes in behavior, personality and social skills. People often quickly deteriorate and usually die about three years after diagnosis; there is also no effective treatment for FTD.

Since mutated tau impairs synapses—the connections between neurons—by reducing the size of NMDA receptors, “boosting the function of remaining NMDA receptors may help restore synaptic firing, and reverse behavioral abnormalities,” said Roberson.

Roberson’s, along with others’ work presented at the Society of Neuroscience meeting, focused on using animal models that mimic developing tau pathology. “These new mouse models, which contain both tau tangles and amyloid plaques” said Dr. Li, “offer the possibility of more accurately testing therapies directed at delaying the onset of amyloid beta plaques, tau accumulation and neuronal loss, all characteristic features of Alzheimer’s.”

Are clinical trials next?

Potentially, yes. “This arena of academic research has been ongoing for several years—it’s a younger area in terms of involvement of drug discovery,” said Sangram Sisodia, Ph.D., director of the Center for Molecular Neurobiology at the University of Chicago. “But I believe there is growing interest in pharma companies about targeting tau.

“The tau protein plays an incredibly complex role in the development of Alzheimer’s and other neurodegenerative diseases,” said Sisodia. “We are in the early stages of understanding that role, which will be crucial for developing effective preventions or treatments.”

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sequential memory

Posted in Alzheimer's Disease, Neurodegenerative Diseases, Neuroscience, tagged , , on October 25, 2015| Leave a Comment »

sequential memory

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Is your thinking chaotic? There’s a model for that.

How the mind processes sequential memory may help understand psychiatric disorders
October 21, 2015

http://www.kurzweilai.net/is-your-thinking-chaotic-theres-a-model-for-that?utm_source=KurzweilAI+Weekly+Newsletter_147a5a48c1-9a20162408-282099089

A representation of a stable sequential working memory; different information items or memory patterns are shown in different colors. (credit: Image adopted from Rabinovich, M.I. et al. (2014)

Try to remember a phone number. You’re now using “sequential memory,” in which your mind processes a sequence of numbers, events, or ideas. It underlies how people think, perceive, and interact as social beings. To understand how sequential memory works, researchers have built mathematical models that mimic this process.

Cognitive modes

Taking this a step further, Mikhail Rabinovich, a physicist and neurocognitive scientist at the University of California, San Diego, and a group of researchers have now mathematically modeled how the mind switches among different ways of thinking about a sequence of objects, events, or ideas that are based on the activity of “cognitive modes.”

The new model, described in an open-access paper in the journal Chaos, may help scientists understand a variety of human psychiatric conditions that may involve sequential memory, including obsessive-compulsive disorder, bipolar, and attention deficit disorder, schizophrenia and autism.

Cognitive modes are the basic states of neural activity. Thinking, perceiving, and any other neural activity involve various parts of the brain that work together in concert, taking on well-defined patterns.

Binding process

When the mind has sequential thoughts, the cognitive modes underlying neural activity switch among different modalities. This switching is called a binding process, because the mind “binds” each cognitive mode to a certain modality.

Consider the TV show Limitless. In the show, FBI consultant Brian Finch, aided by the fictional cognitive enhancer NZT, is able to fluidly switch between complex sets of information (modalities), such as phone numbers, using different cognitive modes — rapidly processing a series of phone numbers of suspects on a screen, or analyzing a complex diagram showing potential criminal connections, then explaining it to colleagues, all without losing a beat.

In the new analysis, the mathematicians proved a theorem to show that in their model, this binding process is robust and able to withstand perturbations from the random disturbances in the brain. Your mind is full of other irregular neural signals — from things like other neural processes or external, sensory stimuli and distractions — but if they’re not too big, they don’t affect the thinking process.

This model could be used to better understand a variety of psychiatric disorders, such as obsessive-compulsive disorder, bipolar disorder, and attention deficit disorder, Rabinovich said. The way the mind binds to different modalities, and how such binding depends on time, may be related to conditions such as autism and schizophrenia. For example, some experiments suggest that for people with these conditions, the capacity of sequential binding memory is smaller.

Rabinovich worked with Valentin Afraimovich and Xue Gong, mathematicians at the Autonomous University of San Luis Potosi in Mexico and Ohio University, respectively.

Abstract of Sequential memory: Binding dynamics

Temporal order memories are critical for everyday animal and human functioning. Experiments and our own experience show that the binding or association of various features of an event together and the maintaining of multimodality events in sequential order are the key components of any sequential memories—episodic, semantic, working, etc. We study a robustness of binding sequential dynamics based on our previously introduced model in the form of generalized Lotka-Volterra equations. In the phase space of the model, there exists a multi-dimensional binding heteroclinic network consisting of saddle equilibrium points and heteroclinic trajectories joining them. We prove here the robustness of the binding sequential dynamics, i.e., the feasibility phenomenon for coupled heteroclinic networks: for each collection of successive heteroclinic trajectories inside the unified networks, there is an open set of initial points such that the trajectory going through each of them follows the prescribed collection staying in a small neighborhood of it. We show also that the symbolic complexity function of the system restricted to this neighborhood is a polynomial of degree L − 1, where L is the number of modalities.

references:

related:

Topics: Cognitive Science/Neuroscience

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Brain and Cognition

Posted in Alzheimer's Disease, Clinical & Translational, Diabetes Mellitus, Neurological Diseases, Neuroscience, tagged , , , , , on October 14, 2015| Leave a Comment »

Brain and Cognition

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Brain activity may be as unique as fingerprints

Tue, 10/13/2015 – Bill Hathaway, Yale Univ.

http://www.rdmag.com/news/2015/10/brain-activity-may-be-unique-fingerprints?et_cid=4877245&et_rid=535648082

Image: Michael S. Helfenbeing/Shutterstock

A person’s brain activity appears to be as unique as his or her fingerprints, a new Yale Univ.-led imaging study shows. These brain “connectivity profiles” alone allow researchers to identify individuals from the fMRI images of brain activity of more than 100 people, according to the study published in Nature Neuroscience.

“In most past studies, fMRI data have been used to draw contrasts between, say, patients and healthy controls,” said Emily Finn, a PhD student in neuroscience and co-first author of the paper. “We have learned a lot from these sorts of studies, but they tend to obscure individual differences which may be important.”

Finn and co-first author Xilin Shen, under the direction of R. Todd Constable, professor of diagnostic radiology and neurosurgery at Yale, compiled fMRI data from 126 subjects who underwent six scan sessions over two days. Subjects performed different cognitive tasks during four of the sessions. In the other two, they simply rested. Researchers looked at activity in 268 brain regions: specifically, coordinated activity between pairs of regions. Highly coordinated activity implies two regions are functionally connected. Using the strength of these connections across the whole brain, the researchers were able to identify individuals from fMRI data alone, whether the subject was at rest or engaged in a task. They were also able to predict how subjects would perform on tasks.

Finn said she hopes that this ability might one day help clinicians predict or even treat neuropsychiatric diseases based on individual brain connectivity profiles.

Brain Activity Identifies Individuals

By Kerry Grens

Neural connectome patterns differ enough between people to use them as a fingerprint.

New Alzheimer’s Gene Identified

Megan Brooks

http://www.medscape.com/viewarticle/852556

Researchers have identified a new gene involved in the immune system that increases the risk for Alzheimer’s disease (AD), providing a potential new target for prevention and treatment.

They found that older adults at risk for AD and those with the disease who carry a specific variant in the interleukin-1 receptor accessory protein (IL1RAP) had higher rates of amyloid plaque accumulation in the brain over 2 years. The effect of the variant was stronger than the well-known AD risk allele APOE ε4.

“These findings suggest that targeting the IL1RAP immune pathway may be a viable approach for promoting the clearance of amyloid deposits and fighting an important cause of progression in Alzheimer’s disease,” Andrew J. Saykin, PsyD, director of the Indiana Alzheimer Disease Center, Indianapolis, and the national Alzheimer’s Disease Neuroimaging Initiative Genetics Core, said in a statement.

The study was published in the October 1 issue of Brain.

Novel Association

The researchers conducted a genome-wide association study of longitudinal changes in brain amyloid burden measured by florbetapir positron emission tomography (PET) in nearly 500 individuals. They assessed the levels of brain amyloid deposits at an initial visit and again 2 years later.

Study participants came from the Alzheimer’s Disease Neuroimaging Initiative, the Indiana Memory and Aging Study, the Religious Orders Study, and the Rush Memory and Aging Project, all longitudinal studies of older adults representing clinical stages along the continuum from normal aging to AD.

As expected, APOE ε4 was associated with higher rates of amyloid plaque buildup. However, they also identified a novel association between a single nucleotide polymorphism in IL1RAP (rs12053868-G) and higher rates of amyloid accumulation, independent of APOE ε4.

Carriers of the IL1RAP rs12053868-G variant showed accelerated cognitive decline and were more likely to progress from mild cognitive impairment to AD. They also showed greater longitudinal atrophy of the temporal cortex, which is involved in memory and had a lower level of microglial activity as measured by PET scans, the researchers report.

“This was an intriguing finding because IL1RAP is known to play a central role in the activity of microglia, the immune system cells that act as the brain’s ‘garbage disposal system’ and the focus of heavy investigation in a variety of neurodegenerative diseases,” Vijay K. Ramanan, MD, PhD, postdoctoral researcher at the Indiana University School of Medicine, Indianapolis, who worked on the study, said in the statement.

“These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process,” the investigators write.

The study was supported by the National Institute on Aging and a consortium of private partners through the Foundation for the National Institutes of Health. Several authors disclosed relationships with pharmaceutical companies. A complete list can be found with the original article.

Brain. 2015;138:3076-3088. Abstract

Cognitive Impairments in Elderly Diabetic Patients: Understanding the Risks for Better Management

Medscape Medical News from the

Visit Medscape in Hall B Booth #B13:31

Medscape Diabetes & Endocrinology

COMMENTARY

Lyse Bordier, MD

http://www.medscape.com/viewarticle/852112

Editor’s Note: The following is an edited, translated transcript of a presentation by Professor Lyse Bordier, a diabetologist at Military Hospital Bégin, Saint-Mandé, France, summarizing her lecture at the European Association for the Study of Diabetes (EASD) 2015 AnnualMeeting in Stockholm, Sweden.

Hello. I am Professor Lyse Bordier. I work at the Bégin Military Hospital, in Saint-Mandé, France, and I had the pleasure of participating in a symposium organized by the EASD 2015 conference in Stockholm on elderly patients, specifically on cognitive impairments.

A Public Health Problem

Dementia and cognitive impairments are a major problem; Alzheimer disease accounts for 70% of all cases of dementia. The other main causes are vascular dementias and mixed dementias. They are a real public health problem; it is estimated that, in the United States, 5.2 million people have this condition, and worldwide, every 7 seconds, a new case of dementia is diagnosed.[1,2] In France, for example, it was estimated in 2010 that 750,000-850,000 people had dementia and that this figure will increase by a factor of 2.4 by the year 2050.

Diabetes is an important contributor to the development of cognitive impairments, all the way up to dementia. In Europe, it is estimated that nearly 25% of people over age 85 years have dementia. Its prevalence and incidence are higher in women than in men.[2] We know that the complications of diabetes have changed over the years and that acute metabolic complications are, in the end, much less important. With the improvement in life expectancy in our diabetic patients, who are now better treated thanks to better therapeutic management, new complications have arisen, such as renal failure, heart failure, and, of course, geriatric complications, which are, in large part, cognitive disorders.[3]

Prevalence Underestimated by Physicians

These cognitive impairments are common and largely underestimated. This was clearly shown in the GERODIAB study,[4] which included a cohort of 987 patients over the age of 70 years. At inclusion, the physicians reported that 11% of their patients had cognitive impairments and that 3% had dementia. In actual fact, 25% of the patients had impaired cognitive functions, with a Mini-Mental State Examination (MMSE) score under 25. The prevalence is therefore significantly underestimated by physicians.

Cognitive impairments are more prevalent and more severe in diabetics than in nondiabetics. It is estimated that the risk for cognitive impairments and that for dementia are 20% to 70% and 60% higher, respectively, in the presence of diabetes.[5] Furthermore, the risk for Alzheimer dementia is considerable, it being 40% higher in diabetics. As expected (given the combination of the other cardiovascular risk factors), the increase in the risk is even greater for vascular dementia, with an odds ratio of 2.38.[6]

Mechanisms

What are the mechanisms in the development of cognitive impairments and dementia? There are many mechanisms, and they are often poorly understood. Hyperglycemia plays a very important role as a direct result of oxidative stress, of advanced glycation end-products, but also as a result of micro- and macroangiopathy, hypertension, and dyslipidemia.[7,8] Other major factors, such as hypoglycemia,[9-12]play an extremely important role in the development of cognitive impairments. As well, a great deal of literature has been published lately on the role of inflammation[13] and genetic factors. Another widely known aspect is insulin resistance, which increases the risk for dementia at a fairly early stage by 40%[14,15]; this already during the metabolic syndrome, even before the onset of type 2 diabetes.

http://img.medscape.com/article/852/112/852112-Figure1.jpg

Figure. Multiple and poorly understood mechanisms of cognitive impairments and dementia. HTA = arterial hypertension. Adapted from Buysschaert M, et al.[16]

What Are the Consequences of Cognitive Impairments?

Cognitive impairments lead to a number of complications, including a reduction in life expectancy. In the GERODIAB cohort, we found, after 2 years of follow-up, that the mortality rate was twice as high in the patients with an MMSE score <24 compared with those with an MMSE score >24. In this study, the patients with a lower MMSE score had less well-controlled diabetes, were usually treated with insulin, and had heart failure and cerebrovascular complications more often. Very surprisingly, hypoglycemia was not more prevalent in these patients, perhaps because, being less independent, they were better managed by care teams.[17]

Cognitive impairments lead to geriatric complications, such as malnutrition, falls, and a loss of autonomy. They also promote social and family isolation and iatrogenic accidents, as well as depression, which can both mask cognitive impairments and exacerbate an underlying dementia. Another important aspect is that cognitive impairments increase the risk for hypoglycemia. This has been shown very clearly in all of the studies. There is, in fact, a bidirectional link between dementia and hypoglycemia: Hypoglycemia doubles the risk for dementia, and dementia triples the risk for hypoglycemia.[18]

Screening and Management

What do we do when a patient presents with cognitive impairments? First, they should be identified so that they can be managed. We need to be vigilant for certain little signs: changes in the patient’s behavior (eg, a patient who forgets his appointments, whose personal hygiene has declined, who is less diligent in keeping his blood glucose diary, and, lastly, who has an unexplained diabetic imbalance). We should also know how to use simple tests, such as the MMSE, which provides an overall assessment of space-time orientation, cognitive functions, language functions, and calculation, and how to assess the patient’s autonomy and loss of autonomy.[19] Next, we should, as per the recommendations of the American Diabetes Association[20] and the EASD, individualize the glycemic goals, taking into account, in the most fragile, elderly patients, cognitive status, the level of autonomy, depression, nutritional status—in particular, sarcopenia, which can coexist with obesity, and the risk for hypoglycemia.[21]

We should therefore avoid overtreating the most fragile patients (those at greatest risk for hypoglycemia), but neither should we undertreat patients who have a long life expectancy and who could develop micro- and macroangiopathic complications.

One last aspect, which is very important, is the family. Help needs to be provided to prevent the patient’s loss of autonomy.[21] Lastly, I think that cognitive decline should be added to the already long list of degenerative complications of diabetes.

PDGFR-ß Plays a Key Role in the Ectopic Migration of Neuroblasts in Cerebral Stroke

Hikari Sato et al.
The neuroprotective agents and induction of endogenous neurogenesis remain as the urgent issues to be established for the care of cerebral stroke. Platelet-derived growth factor receptor beta (PDGFR-ß) is mainly expressed in neural stem/progenitor cells (NSPCs), neurons and vascular pericytes of the brain; however, the role in pathological neurogenesis remains elusive. This review examined the role of PDGFR-ß in the migration and proliferation of NSPCs after stroke.

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