Posts Tagged ‘Tau protein’

Alzheimer’s Disease – tau art thou, or amyloid

Larry H. Bernstein, MD, FCAP, Curator



Alzheimer’s Disease and Tau

Pathogenic Mechanisms and Therapeutic Approaches

Organizers: Robert Martone (St. Jude Children’s Research Hospital) and Sonya Dougal (The New York Academy of Sciences)Presented by the Brain Dysfunction Discussion Group

Reported by Caitlin McOmish | Posted February 2, 2016


Microtubule-associated protein tau helps maintain the stability and flexibility of microtubules in neuronal axons. Alternative splicing of the tau gene, MAPT, produces 6 isoforms of tau in the brain and many more in the peripheral nervous system. Tau can be phosphorylated at over 30 sites, and it undergoes many posttranslational modifications to operate as a substrate for multiple enzymes. However, tau also mediates pathological functions including neuroinflammatory response, seizure, and amyloid-β (Aβ) toxicity, and tau pathology is a hallmark of conditions including frontotemporal dementia, traumatic brain injury (TBI), Down syndrome, focal cortical dysplasia, and Alzheimer’s disease (AD), as well as some tumors and infections. On September 18, 2015, speakers at the Brain Dysfunction Discussion Group’s Alzheimer’s Disease and Tau: Pathogenic Mechanisms and Therapeutic Approaches symposium discussed the mechanisms by which tau becomes pathological and how the pathology spreads. They also described emerging therapeutic strategies for AD focused on tau.

Microtubule-associated protein tau has a complex biology, including multiple splice variants and phosphorylation sites. Tau is a key component of microtubules, which contribute to neuronal stability. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles. (Image presented by Robert Martone courtesy of the National Institute on Aging)


Tau is ubiquitous in the brain, with widespread effects, but has historically been overlooked as a driving force in AD. In his introduction to the symposium, Robert Martone from St. Jude Children’s Research Hospital highlighted tau’s activity and emergence as a treatment target for this devastating disorder. Hyperphosphorylated tau (p-tau) has long been recognized as a principle component of neurofibrillary tangles in AD; tau monomers are misfolded into oligomers that form tau filaments. As Hartmuth Kolb from Johnson & Johnson explained, the development in 2012 of a tau-specific positron emission tomography (PET) tracer led to important insights into the presence and spread of tau pathology over the course of tauopathies, including AD, in humans. Notably, researchers demonstrated that tau pathology propagates through the brain in a predictable pattern, corresponding to the Braak stages of AD.

Tau pathology spreads through the brain in a predictable pattern. Abnormal tau protein is first observed in the transentorhinal region (stages I and II) and spreads to the limbic regions in stages III and IV, when early signs of AD begin to be observed. Pathology subsequently extends throughout the neocortex, driving fully developed AD. This staging was first described by Braak and Braak in 1991. (Image courtesy of Hartmuth Kolb)


It is likely that the symptoms of AD are produced by the combined effects of tau and Aβ pathologies. George Bloom from the University of Virginia described how Aβ and tau interact to cause mature neurons to reenter the cell cycle, leading to cell death. In a healthy brain, insulin acts as a gatekeeper that maintains adult neurons in the G0 phase after the cells permanently exit the cell cycle. In AD, amyloid oligomers sequester neuronal insulin receptors, causing insulin resistance. In parallel, tau phosphorylation at key sites—pY18 (fyn site), pS409 (PKA site), pS416 (CAM Kinase site), and pS262—drives mTOR signaling at the plasma membrane but not at the lysosome, resulting in cell cycle reentry. In a normal cell, activation of mTOR at the lysosome overrides the cell cycle reentry signal—creating an important regulatory mechanism for maintaining healthy neurons. However, lysosomal activation of mTOR is insulin dependent and thus affected by Aβ-induced insulin insensitivity. Amyloid oligomers, via insulin regulation, release the brakes on a cascade of events driven by p-tau that leads to cell cycle reentry and cell death.

Hallmark dysfunction produced by Aβ is dependent on tau. Pathological Aβ drives the formation of p-tau in the brain, resulting in synaptic dysfunction, cell death, and broad neurocognitive symptoms. This process can be influenced by a range of factors including genetic predisposition, environmental risk factors, and biochemical signaling pathways. (Image courtesy of George Bloom)


Khalid Iqbal from the New York State Institute for Basic Research in Developmental Disabilities described research showing that p-tau spreads through the brain in a rodent model, well beyond the injection site, in a prion-like manner, and that the spread of pathology can be mitigated by the addition of PP2A—a phosphatase known to be decreased in gray and white matter in AD. PP2A regulation is affected in AD, stroke, and brain acidosis, providing a link between these disorders and tau pathology.

Discussion of the pathophysiology of AD commonly focuses on Aβ plaques and neurofibrillary tangles (NFTs) composed of misassembled hyperphosphorylated tau; it has generally been thought that these plaques and tangles are the primary causes of symptoms. However, recent evidence indicates that oligomeric variants of tau are actually far more toxic than the form of tau present in NFTs. Michael Hutton from Eli Lilly and Company studies the properties needed for tau to become pathological. He used animal models to show that the abnormal p-tau “seed,” from which a prion-like spread develops, must be of a high molecular weight (with at minimum three tau units) and highly phosphorylated to induce healthy tau to become pathological. These characteristics are necessary but not sufficient for effective seeding. There is also evidence that tau pathology propagates via an autocatalytic cycle of seeded aggregation and fragmentation.

Propagation, in addition to requiring a large number of p-tau units in aggregates, may be affected by the isomerization of those monomers. Kun Ping Lu from Harvard Medical School provided data suggesting that cis but not trans pT231-tau is a precursor of tauopathy, linking TBI to the later development of neurodegenerative diseases such as chronic traumatic encephalopathy and AD. He demonstrated a role for Pin1, a phosphorylation-specific prolyl isomerase, in this process using animal models of TBI and AD. Pin1, which is regulated in response to stress, prevents the accumulation of toxic cis p-tau by converting it to the trans isoform, but this process is inhibited in AD and TBI. Lu showed that cis p-tau’s ability to cause and spread neurodegeneration can be blocked by a cis p-tau monoclonal antibody in vitro and in animal models, pointing to the therapeutic potential of targetingcis p-tau for treatment of TBI and AD.

Culturing p-tau seeds in vitro produces a broad array of tau aggregate structures. Marc Diamond from the University of Texas Southwestern Medical Center discussed the diverse structures produced by different tau seeds, which his team has studied in a series of experiments using in vitro models, animal models, and human postmortem analyses. His lab showed that distinct conformations of aggregate seeds propagate stably, infecting normal cells and leading them to acquire abnormal tau aggregates with distinct, reproducible structures and different biochemical properties. In another study, the team showed that the morphology of the p-tau aggregates was related to diagnosis. Seeds sourced from postmortem human tissue produced reliable phenotypes in culture, which tracked with different diagnoses, retroactively predicting biological outcome. Thus, the characteristics of the p-tau seed have a large influence on the biological outcome, providing a new prospect for presymptomatic diagnosis.

Tau seeds obtained from postmortem brain tissue from AD, argyrophilic grain disease (AGD), corticobasal degeneration (CBD), Pick’s disease (PiD), and progressive supranuclear palsy (PSP) produce unique aggregate pathologies in cell culture, including toxic, mosaic, ordered, disordered, and speckled. AD-derived seeds largely produce the speckled phenotype. (Images courtesy of Marc Diamond)


With the mechanisms by which p-tau forms, converts healthy tau, and seeds dysfunction established, the question of how p-tau exits the cell and moves through the brain arises. The pattern of spread and the speed with which the pathology progresses suggests that p-tau propagates trans-synaptically. Nicole Leclerc from the University of Montreal provided evidence to support this view. It is likely, her lab has shown, that tau is secreted and taken up by neurons in an active process, in response to neuronal activity. Tau secretion in vitro increases under conditions such as starvation and lysosomal dysfunction, phenomena found in the early stages of AD. Moreover, hyperphosphorylation appears to increase the targeting of tau to the secretory pathway, potentially accelerating the spread of p-tau. Intriguingly, however, the extracellular tau is hypophosphorylated, suggesting large-scale dephosphorylation during the secretory process. This hypo-tau may activate muscarinic acetylcholine receptors, increasing intracellular Ca2+ and promoting cell death.

These findings suggest that the synapse plays a critical role in the development of AD; the extrasynaptic environment is known to be exquisitely regulated by microglia. The focus of studies into neurodegenerative disorders is often neurons, but genetic studies have repeatedly identified changes in expression of microglial genes in AD, including in one of the leading AD candidate genes, TREM2, demonstrating a fundamental contribution of these cells to AD. Richard Ransohoff of Biogen discussed the importance of this cell type. Microglia enter the brain at around embryonic day (E) 9.5 in rodents and are crucially involved in maintaining brain health. During development the cells play a major role in large-scale synaptic pruning required for effective neural maturation. They are also highly responsive to the environment, and stress in adulthood can reengage microglial synaptic pruning—a process that is adaptive during development but maladaptive in adulthood. The process is regulated by complement system cascades. TGF-β expressed by astrocytes drives neurons to express C1q presynaptically, initiating complement elements to accumulate at the site, ultimately activating microglia to prune the synaptic connection. In AD, inappropriate activation of this cascade may lead to the removal of otherwise healthy connections. Ransohoff described a role for CXCR3, the fractalkine receptor, in regulating reactivity of microglia, and thus mitigating pruning of adult synapses. Regulation of microglia reactivity is driven by epigenetically induced changes in inflammatory response genes. Correspondingly, in the absence of CXCR3, tau pathology is aggravated in htau mice (which express human tau isoforms), suggesting a protective effect of the CXCR3 pathway. Ransohoff closed with the caveat that microglia are not intrinsically helpful or harmful; their properties are context dependent and must be unraveled by empirical observations in appropriate models.

Peter Davies from the Feinstein Institute for Medical Research discussed the need to better incorporate current knowledge into research model design, particularly to develop monoclonal antibodies for the treatment of AD. Monoclonal antibodies are a promising strategy, but translating preclinical findings into successful clinical outcomes will require careful consideration of the context of the early research. Most transgenic animal models for AD express p-tau in all neurons, but such extensive p-tau spread is not found in human AD brains. There are several hurdles to determine the drugs’ efficacy and safety in humans; it is difficult to assess specificity and find appropriate dosages. In a series of studies with a focus on external reproducibility, Davies presented evidence from animal models showing that immunotherapy can block the spread of p-tau but cannot undo pathology already present in the brain. In the htau mouse model several putative antibodies lacked efficacy and in some cases appeared to worsen pathology. These findings underscore the need for both better models and improved understanding of mechanisms of action before moving drugs to the clinic.


The New York Academy of Sciences. Alzheimer’s Disease and Tau: Pathogenic Mechanisms and Therapeutic Approaches. Academy eBriefings. 2015. Available at:



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Neural Networks in Alzheimer’s

Larry H. Bernstein, MD, FCAP, Curator


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

Stephanie Guzowski, Editor

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, France2Ludwig-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

“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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Alzheimer’s Genomic Diagnosis and Treatment

Larry H Bernstein, MD, FCAP


Gene Mutation Protects Against Alzheimer’s

by Greg Miller on 11 July 2012
Brain preserver. A newly discovered gene mutation appears to protect against Alzheimer’s disease. Credit: Alzheimer’s Disease Education and Referral Center/NIA/NIH

A rare mutation that alters a single letter of the genetic code protects people from the

  • memory-robbing dementia of Alzheimer’s disease.

The DNA change may inhibit the buildup of β amyloid, the

  • protein fragment that forms the hallmark plaques in the brains of Alzheimer’s patients.
  • The mutation affects a gene called APP,
  • which encodes a protein that gets broken down into pieces,
  • including β amyloid.

Researchers previously identified more than 30 mutations to APP, none of them good. Several of these changes increase β amyloid formation and cause

•      a devastating inherited form of Alzheimer’s that afflicts people in their 30s and 40s—

•      much earlier than the far more common “late-onset” form of Alzheimer’s

  • that typically strikes people their 70s and 80s.

The new mutation, discovered from whole-genome data from 1795 Icelanders for variations in APP that protect against Alzheimer’s, appears to do the opposite. The mutation interferes with one of the enzymes that breaks down the APP protein and causes a 40% reduction in β amyloid formation

New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease modifying drugs.
Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F.
University of Catania, Viale Andrea Doria 6, Catania, Italy.
Br J Clin Pharmacol. 2012 Apr;73(4):504-17. doi: 10.1111/j.1365-2125.2011.04134.x.

Current approved drug treatments for Alzheimer disease (AD) include

These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop ‘disease modifying drugs’ hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success,

  • it is crucial to have biomarkers for early detection of AD-related brain dysfunction,
    • usable before clinical onset.

Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy,

  • with specific cut off values validated in clinical practice.

Disease modifying drugs developed so far include drugs to

  • reduce β amyloid () production,
  • drugs to prevent Aβ aggregation,
  • drugs to promote Aβ clearance,
  • drugs targeting tau phosphorylation and assembly

None of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from

  • methodological flaws to
  • fundamental understanding of AD pathophysiology and biology.

Diagnostic criteria applicable to presymptomatic stages of AD have now been published.

These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset.

Gene mutation defends against Alzheimer’s disease
Rare genetic variant suggests a cause and treatment for cognitive decline.
Ewen Callaway  11 July 2012

Almost 30 million people live with Alzheimer’s disease worldwide, a staggering health-care burden that is expected to quadruple by 2050. Yet doctors can offer no effective treatment, and scientists have been unable to pin down the underlying mechanism of the disease.
Research published this week offers some hope on both counts – few people carry a genetic mutation that naturally prevents them from developing the condition – 0.5% of Icelanders have a protective gene, as are 0.2–0.5% of Finns, Swedes and Norwegians. Icelanders who carry it have a 50% better chance of reaching age 85, are more than five times more likely to reach it 85 without Alzheimer’s.   The mutation seems to put a brake on the milder mental deterioration that most elderly people experience. Carriers are about 7.5 times more likely than non-carriers to reach the age of 85 without major cognitive decline, and perform better on the cognitive tests that are administered thrice yearly to Icelanders who live in nursing homes.
The discovery not only confirms the principal suspect that is responsible for Alzheimer’s, it also suggests that the disease could be

  • an extreme form of the cognitive decline seen in many older people.

The mutation — the first ever found to protect against the disease — lies in a gene that produces

  • amyloid-β precursor protein (APP),
  • which has an unknown role in the brain

APP was discovered 25 years ago in patients with rare,

  • inherited forms of Alzheimer’s that strike in middle age.
  • In the brain, APP is broken down into a smaller molecule called amyloid-β.

Visible clumps, or plaques, of amyloid-β found in the autopsied brains of patients are a hallmark of Alzheimer’s.
Scientists have long debated whether the plaques are a cause of the neuro­degenerative condition

  • or a consequence of other biochemical changes associated with the disease.

The latest finding supports other genetics studies blaming amyloid-β, according to Rudolph Tanzi, a neurologist at the Massachusetts General Hospital in Boston and a member of one of the four teams that discovered APP’s role in the 1980s.
If amyloid-β plaques were confirmed as the cause of Alzheimer’s, it would bolster efforts to develop drugs that block their formation, says Kári Stefánsson, chief executive of deCODE Genetics in Reykjavik, Iceland, who led the latest research. He and his team first discovered the mutation by comparing the complete genome sequences of 1,795 Icelanders with their medical histories. The researchers then studied the variant in nearly 400,000 more Scandinavians.
This suggests that Alzheimer’s disease and cognitive decline are two sides of the same coin, with a common cause — the build-up of amyloid-β plaques in the brain, something seen to a lesser degree in elderly people who do not develop full-blown Alzheimer’s. A drug that mimics the effects of the mutation, might slow cognitive decline as well as prevent Alzheimer’s.
Stefánsson and his team discovered that the mutation introduces a single amino-acid alteration to APP. This amino acid is close to the site where an enzyme called

  • β-secretase 1 (BACE1) ordinarily snips APP into smaller amyloid-β chunks —
  • and the alteration is enough to reduce the enzyme’s efficiency.

Stefánsson’s study suggests that blocking β-secretase from cleaving APP has the potential to prevent Alzheimer’s, but Philippe Amouyel, an epidemiologist at the Pasteur Institute in Lille, France, says “it is very difficult to identify the

  • precise time when this amyloid toxic effect could still be modified”.

“If this effect needs to be blocked as early as possible in life to protect against Alzheimer’s disease, we will need to propose a new design for clinical trials” to identify an effective treatment.

The results demonstrate that whole-genome sequencing can uncover very rare mutations that might offer insight into common diseases.

  • disease risk, may be determined by genetic variants that slightly tilt the odds of developing disease
  • In this case a rare mutant may provide very key mechanistic insights into Alzheimer’s

Jonsson, T. et al. Nature (2012).
Kang, J. et al. Nature 325, 733–736 (1987).
Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U. & Gajdusek, D. C. Science 235, 877–880 (1987).

BHCE genetic data combined with brain imaging using agent florbetapir connects the BHCE gene to AD plaque buildup. BHCE is an enzyme that breaks down acetylcholine in the brain, which is depleted early in the disease and results in memory loss.

New Alzheimer’s Genes Found
Gigantic Scientific Effort Discovers Clues to Treatment, Diagnosis of Alzheimer’s Disease
By Daniel J. DeNoon
WebMD Health News Reviewed by Laura J. Martin, MD

A massive scientific effort has found five new gene variants linked to Alzheimer’s disease. The undertaking involved analyzing the genomes of nearly 40,000 people with and without Alzheimer’s. This study was undertaken by two separate research consortiums in the U.S. and in Europe, which collaborated to confirm each other’s results.
Four genes had previously been linked to Alzheimer’s. Three of them affect only the risk of relatively rare forms of Alzheimer’s. The fourth is APOE, until now the only gene known to affect risk of the common, late-onset form of Alzheimer’s. Roughly 27% of Alzheimer’s disease can be attributed to the five new gene variants.  Even though Alzheimer’s is a very complex disease, the new findings represent a large chunk of Alzheimer’s risk, according to Margaret A. Pericak-Vance, PhD, of the U.S. consortium –

  • 20% of the causal risk of Alzheimer’s disease and
  • 32% of the genetic risk.

Alzheimer’s Tied to Mutation Harming Immune Response
By GINA KOLATA   Published: November 14, 2012  in NY Times
Alzheimer’s researchers and drug companies have for years concentrated on one hallmark of Alzheimer’s disease: the production of toxic shards of a protein that accumulate in plaques on the brain.
Two groups of researchers working from entirely different starting points have converged on a mutated gene involved in another aspect of Alzheimer’s disease:

  • the immune system’s role in protecting against the disease.

The mutation is suspected of interfering with

  • the brain’s ability to prevent the buildup of plaque.

When the gene is not mutated, white blood cells in the brain spring into action,

  • gobbling up and eliminating the plaque-forming toxic protein, beta amyloid.

As a result, Alzheimer’s can be staved off or averted.  People with the mutated gene have a threefold to fivefold increase in the likelihood of developing Alzheimer’s disease in old age.

Comparing Differences

Dr. Julie Williams’s, Cardiff, Wales (European team leader) report identified CLU and Picalm. A second study published in Nature Genetics, by Philippe Amouyel from Institut Pasteur de Lille in France, pinpointed CLU and CR1. The greatest inherited risk comes from the APOE gene, discovered in 1993 by a team led by Allen Roses, now director of the Deane Drug Discovery Institute at Duke UMC, in Durham, North Carolina.
The findings “are beginning to give us insight into the biology, but I don’t think you can expect treatments overnight,” Dr. Michael Owen (Cardiff, Wales) said. Instead, the genes will show a mosaic of risk, and “the key issue is what hand of cards you’re dealt,” he said.

Promise for Early Diagnosis
BHCE genetic data combined with brain imaging using agent florbetapir connects the BHCE gene to AD plaque buildup. BHCE is an enzyme that breaks down acetylcholine in the brain, which is depleted early in the disease and results in memory loss.

Dr. Bernstein’s comments:

  1. There has been a long history of failure of drugs to slow down the progression of Alzheimer’s.  Regression of the plaques has not corresponded with retention of cognitive ability, which has been behind the arguments over beta amyloid or tau.
  2. We now have two particularly interesting mutations –
    1. ApoE gene mutation that increases risk
    2. APP mutation that quite dramatically affects retention of cognition
β-amyloid fibrils.

β-amyloid fibrils. (Photo credit: Wikipedia)

English: PET scan of a human brain with Alzhei...

English: PET scan of a human brain with Alzheimer’s disease (Photo credit: Wikipedia)

Depiction of amyloid precursor protein process...

Depiction of amyloid precursor protein processing, created by I. Peltan Ipeltan (Photo credit: Wikipedia)

English: Diagram of how microtubules desintegr...

English: Diagram of how microtubules desintegrate with Alzheimer’s disease Français : La protéine Tau dans un neurone sain et dans un neurone malade Español: Esquema que muestra cómo se desintegran los microtúbulos en la enfermedad de Alzheimer (Photo credit: Wikipedia)

English: Histopathogic image of senile plaques...

English: Histopathogic image of senile plaques seen in the cerebral cortex in a patient with presenile onset of Alzheimer disease. Bowdian stain. The same case as shown in a file “Alzheimer_dementia_(1)_presenile_onset.jpg”. (Photo credit: Wikipedia)


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Curated by: Dr. Venkat S. Karra, Ph.D.

A human brain showing frontotemporal lobar deg...

The number of patients with dementia have been increasing exponentially with the aging of society.  The development of AD research has clarified that the pathogenesis of AD is initiated by amyloidosis with secondary tauopathy and provided a strategy for investigating drugs that may improve or cure AD.

Mild cognitive impairment (MCI) as a prodromal stage of AD and the pathogenesis of Dementia with Lewy bodies (DLB) and Frontotemporal lobar degeneration (FTLD) as a non-AD type dementia have also been elucidated. Currently, a consortium study by the Alzheimer Disease Neuroimaging initiative (ADNI) is being performed to establish global clinical evidence regarding a neuropsychiatric test battery, CSF biomarkers, neuroimaging including MRI, FDG-PET, and amyloid PET to predict progression from MCI to AD and to promote studies of basic therapy for AD [1].

Several new biomarkers such as Aβ oligomer, α-synuclein, and TDP-43 are now under investigation for further determination of their usefulness to detect AD and other non-AD type dementia.

Cerebrospinal Fluid Aβ40, Aβ42, Tau, and Phosphorylated Tau biomarkers have been used for a clinical diagnosis of AD, discrimination from the Vascular dementia (VaD) and non-AD type dementia, exclusion of treatable dementia and MCI, prediction of AD onset and evaluation of the clinical trials of an anti-Aβ antibody, Aβ vaccine therapy, and secretase inhibitors [2–4].

In the current study Schoonenboom et al., [10] conducted a large cohort of patients with different types of dementia to determine how amyloid β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels behave in CSF.

Aβ is produced mainly in the nerve cells of the brain, and it is secreted about 12 hours later into the CSF, then excreted through the blood-brain barrier 24 hours later into blood (Aβ clearance), and finally degraded in the reticuloendothelial system. Aβ levels are regulated in strict equilibrium among the brain, CSF, and blood [6, 7]. Aβ levels are high while awake and low while a sleep suggesting the presence of a daily change in the CSF Aβ amounts and it is because Aβ amounts in CSF are controlled by orexin and thus collection of CSF by lumbar puncture early in morning in a fasting state is recommended [5].

In AD brains, Aβ42 forms insoluble amyloids and accumulates as insoluble amyloid fibrils in the brain. The reason Aβ42 levels are decreased in the CSF of AD patients is considered to be caused by deterioration of physiologic Aβ clearance into the CSF in AD brains [2, 3]. CSF total tau levels increase slightly with aging. However, CSF tau levels show a 3-fold greater increase in AD patients than in normal controls [8].

It is thought that the rise in CSF total tau is related to degeneration of axons and neurons and to severe destructive disease of the nervous system. Several diseases show slightly increased tau levels such as VaD, multiple sclerosis, AIDS dementia, head injury, and tauopathy. However, CSF tau levels show significant increases in Creutzfeldt-Jakob disease (CJD) and meningoencephalitis [8].

These biomarkers can be measured with an Amyloid ELISA Kit (Wako), which is commercially available and used worldwide. The ELISA kit was developed in Japan by Suzuki et al. and shows extremely high sensitivity and reproducibility [9]. INNOTEST β-AMYLOID1-42 (Innogenetics), for Aβ42 is used widely in Europe and America.

Several assay kits for total tau and phosphorylated tau are also used for the measurement of CSF tau. Currently, total tau is measured using INNOTEST hTau Ag (Innogenetics). There are 3 ELISA systems for measurement of phosphorylated tau that recognize the special phosphorylation sites at Ser199 (Mitsubishi Chemical Corp.), Thr181 (Innogenetics) and Thr231 (Applied NeuroSolutions Inc.), and phosphorylated tau levels are increased in CSF of AD on assays using these kits. Of these 3 kits, INNOTEST PHOSPHO-TAU (181) (Innogenetics) is commercially available and used widely. Recently, INNO-BIA AlzBio3 by Innogenetics has been able to measure Aβ1-42, total tau, and P-tau181P simultaneously in 75 μL of CSF, which is a very small amount of CSF.

In the current study researchers used the following strategy to collect Baseline CSF and Aβ42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA:

Types of patients with Alzheimer disease (AD) = 512 patients
Types of patients with other types of dementia (OD) = 272 patients
Types of patients with a psychiatric disorder (PSY) = 135 patients
Types of patients with subjective memory complaints (SMC) = 275 patients
Autopsy was obtained in a subgroup of about 17 patients.

The study suggested that CSF Aβ42, t-tau, and p-tau are useful in differential dementia diagnosis, whereas in DLB, FTLD, VaD, and CBD, a substantial group exhibited a CSF AD biomarker profile, which requires more autopsy confirmation in the future.

The study found a correct classification of patients with AD (92%) and patients with OD (66%)  when CSF Aβ42 and p-tau were combined.
Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%.

Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau.

CSF AD biomarker profile was seen in

47% of patients with dementia with Lewy bodies (DLB),

38% in corticobasal degeneration (CBD), and

30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD).

PSY and SMC patients had normal CSF biomarkers in 91% and 88%.

Older patients are more likely to have a CSF AD profile.

Concordance between clinical and neuropathologic diagnosis was 85%.

CSF markers reflected neuropathology in 94%.

The study concluded that CSF Aβ42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future.


1. R. C. Petersen, P. S. Aisen, L. A. Beckett et al., “Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization,” Neurology, vol. 74, no. 3, pp. 201–209, 2010.

2. M. Shoji and M. Kanai, “Cerebrospinal fluid Aβ40 and Aβ42: natural course and clinical usefulness,” Journal of Alzheimer’s Disease, vol. 3, no. 3, pp. 313–321, 2001.

3. M. Shoji, M. Kanai, E. Matsubara et al., “The levels of cerebrospinal fluid Aβ40 and Aβ42(43) are regulated age-dependently,” Neurobiology of Aging, vol. 22, no. 2, pp. 209–215, 2001.

4. M. Kanai, E. Matsubara, K. Isoe et al., “Longitudinal study of cerebrospinal fluid levels of tau, Aβ1-40, and Aβ1-42(43) in Alzheimer’s disease: a study in Japan,” Annals of Neurology, vol. 44, no. 1, pp. 17–26, 1998.

5. J. E. Kang, M. M. Lim, R. J. Bateman et al., “Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle,” Science, vol. 326, no. 5955, pp. 1005–1007, 2009.

6. M. Shoji, T. E. Golde, J. Ghiso et al., “Production of the Alzheimer amyloid β protein by normal proteolytic processing,” Science, vol. 258, no. 5079, pp. 126–129, 1992.

7. R. J. Bateman, E. R. Siemers, K. G. Mawuenyega et al., “A γ-secretase inhibitor decreases amyloid-β production in the central nervous system,” Annals of Neurology, vol. 66, no. 1, pp. 48–54, 2009.

8. M. Shoji, E. Matsubara, T. Murakami et al., “Cerebrospinal fluid tau in dementia disorders: a large scale multicenter study by a Japanese study group,” Neurobiology of Aging, vol. 23, no. 3, pp. 363–370, 2002.

9. N. Suzuki, T. T. Cheung, X. D. Cai et al., “An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP) mutants,” Science, vol. 264, no. 5163, pp. 1336–1340, 1994.


10. N.S.M. Schoonenboom et al., Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort

For further insight read the following excellent review article by M. Shoji

Biomarkers of Dementia

Special thanks to Wikipedia for excellent relevant pictures and keyword links.

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Curated by: Dr. Venkat S. Karra, Ph.D

Auguste Deter. Alois Alzheimer's patient in No...

Nuerodegenertive disease – Alzheimer’s – is presumed to be caused by the accumulation of β-amyloid.

The diagnosis of Alzheimer’s disease focuses on

β-amyloid protein and

tau protein

Though much attention is on radiolabeled markers, imaging βamyloid is problematic because many cognitively normal elderly have large amounts of β-amyloid in their brain, and appear as “positives” in the imaging tests.

At the same time therapeutic approaches for Alzheimer’s disease have not been focused much on the process of producing a neurofibrillary tangle composed on tau protein.

Various brain sections showing tau protein

Various brain sections showing tau protein (Photo credit: WBUR)

Now the BUSM researchers identified a new group of proteins, termed RNA-binding proteins, which accumulate in the brains of patients with Alzheimer’s disease, and are present at much lower levels in subjects who are cognitively intact.

The researchers believe this work opens up novel approaches to diagnose and stage the likelihood of progression by quantifying the levels of these RNA-binding protein biomarkers that accumulate in the brains of Alzheimer patients.

The group found two different proteins, both of which show striking patterns of accumulation. “Proteins such as TIA-1 and TTP, accumulate in neurons that accumulate tau protein, and co-localize with neurofibrillary tangles. These proteins also bind to tau, and so might participate in the disease process,” explained senior author Benjamin Wolozin, MD, PhD, a professor in the departments of pharmacology and neurology at BUSM.

“A different RNA binding protein, G3BP, accumulates primarily in neurons that do not accumulate pathological tau protein.

This observation is striking because it shows that neurons lacking tau aggregates (and neurofibrillary tangles) are also affected by the disease process,” he added.

Wolozin’s group also pursued the observation that some of the RNA binding proteins bind to tau protein, and tested whether one of these proteins, TIA-1, might contribute to the disease process.

‘Stress’ induced aggregation of RNA-binding proteins

Previously, scientists like Tara Vanderweyde et. al., have demonstrated that TIA-1 spontaneously aggregates in response to stress as a normal part of the stress response. They examined the relationship between Stress Granules (SGs) and neuropathology in brain tissue from P301L Tau transgenic mice, as well as in cases of Alzheimer’s disease and FTDP-17.

Stress Granules (SGs) are ‘Stress’ induced aggregation of RNA-binding proteins.

The pattern of SG pathology differed dramatically based on the RNA-binding protein examined. SGs positive for T-cell intracellular antigen-1 (TIA-1) or tristetraprolin (TTP) initially did not co-localize with tau pathology, but then merge with tau inclusions as disease severity increases. In contrast, G3BP (ras GAP-binding protein) identifies a novel type of molecular pathology that shows increasing accumulation in neurons with increasing disease severity, but often is not associated with classic markers of tau pathology. TIA-1 and TTP both bind phospho-tau, and TIA-1 overexpression induces formation of inclusions containing phospho-tau. These data suggest that SG formation might stimulate tau pathophysiology.

Thus, study of RNA-binding proteins and SG biology highlights novel pathways interacting with the pathophysiology of AD.

With this understanding, Wolozin and his colleagues hypothesize that since TIA-1 binds tau, it might stimulate tau aggregation during the stress response. They introduced TIA-1 into neurons with tau protein, and subjected the neurons to stress. Consistent with their hypothesis, tau spontaneously aggregated in the presence of TIA-1, but not in the absence. Thus, the group has potentially identified an entirely novel mechanism to induce tau aggregates de novo.

In future work, the group hopes to use this novel finding to understand how neurofibrillary tangles for in Alzheimer’s disease and to screen for novel compounds that might inhibit the progression of Alzheimer’s disease.

They believe that it may open up novel approaches to diagnose and stage the progression likelihood of the disease in Alzheimer patients.

Curated by: Dr. Venkat S. Karra, Ph.D

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