Posts Tagged ‘Alzheimer’

Brain and Cognition

Larry H. Bernstein, MD, FCAP, Curator


Brain activity may be as unique as fingerprints

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

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

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


Lyse Bordier, MD

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]


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.

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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TyrNovo’s Novel and Unique Compound, named NT219, selectively Inhibits the process of Aging and Neurodegenerative Diseases, without affecting Lifespan

Reporter: Aviva Lev-Ari, PhD, RN

A step toward development of drugs for diseases such as Alzheimer’s, Parkinson’s and Huntington’s

December 3, 2013


Jerusalem – A successful joint collaboration between researchers at The Hebrew university of Jerusalem and the startup company TyrNovo may lead to a potential treatment of brain diseases. The researchers found that TyrNovo’s novel and unique compound, named NT219, selectively inhibits the process of aging in order to protect the brain from neurodegenerative diseases, without affecting lifespan. This is a first and important step towards the development of future drugs for the treatment of various neurodegenerative maladies.
Human neurodegenerative diseases such as Alzheimer’s, Parkinson’s andHuntington’s diseases share two key features: they stem from toxic proteinaggregation and emerge late in life. The common temporal emergence pattern exhibited by these maladies proposes that the aging process negatively regulates protective mechanisms that prevent their manifestation early in life, exposing the elderly to disease. This idea has been the major focus of the work in the laboratory of Dr. Ehud Cohen of the Department of Biochemistry and Molecular Biology, at The Hebrew University of Jerusalem‘s Faculty of Medicine.
Dr. Cohen’s first breakthrough in this area occurred when he discovered, working with Dr. Ehud Cohenworms, that reducing the activity of the signaling mechanism conveyed through insulin and the growth hormone IGF1, a major aging regulating pathway, constituted a defense against the aggregation of the Aβ protein which is mechanistically-linked with Alzheimer’s disease. Later, he found that the inhibition of this signaling route also protected Alzheimer’s-model mice from behavioral impairments and pathological phenomena typical to the disease. In these studies, the path was reduced through genetic manipulation, a method not applicable in humans.
Dr. Hadas Reuveni, the CEO of TyrNovo, a startup company formed for the clinical development of NT219, and Professor Alexander Levitzki from the Department of Biological Chemistry at The Hebrew University, with their research teams, discovered a new set of compounds that inhibit the activity of the IGF1 signaling cascade in a unique and efficient mechanism, primarily for cancer treatment, and defined NT219 as the leading compound for further development.
Now, in a fruitful collaboration Dr. Cohen and Dr. Reuveni, together with Dr. Cohen’s associates Tayir El-Ami and Lorna Moll, have demonstrated that NT219 efficiently inhibits IGF1 signaling, in both worms and human cells. The inhibition of this signaling pathway by NT219 protected worms from toxic protein aggregation that in humans is associated with the development of Alzheimer’s or Huntington’s disease.
The discoveries achieved during this project, which was funded by the Rosetrees Trust of Britain, were published this week in the journal Aging Cell (“A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity”). The findings strengthen the notion that the inhibition of the IGF1 signaling pathway has a therapeutic potential as a treatment for neurodegenerative disorders. They also point at NT219 as the first compound that provides protection from neurodegeneration-associated toxic protein aggregation through a selective manipulation of aging.
Cohen, Reuveni and Levitzki have filed a patent application that protects the use of NT219 as a treatment for neurodegenerative maladies through Yissum, the technology transfer company of The Hebrew University. Dr. Gil Pogozelich, chairman of Goldman Hirsh Partners Ltd., which holds the controlling interest in TyrNovo, says that he sees great importance in the cooperation on this project with The Hebrew University, and that TyrNovo represents a good example of how scientific and research initiatives can further health care together with economic benefits.
Recently, Dr. Cohen’s laboratory obtained an ethical approval to test the therapeutic efficiency of NT219 as a treatment in Alzheimer’s-model mice, hoping to develop a future treatment for hitherto incurable neurodegenerative disorders.


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Reporter: Aviva Lev-Ari, PhD, RN

J R Soc Interface. 2013 Feb 20;10(82):20130006. doi: 10.1098/rsif.2013.0006. Print 2013 May 6.

The inverse association of cancer and Alzheimer’s: a bioenergetic mechanism.

Demetrius LASimon DK.


Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.


The sporadic forms of cancer and Alzheimer’s disease (AD) are both age-related metabolic disorders. However, the molecular mechanisms underlying the two diseases are distinct: cancer is described by essentially limitless replicative potential, whereas neuronal death is a key feature of AD. Studies of the origin of both diseases indicate that their sporadic forms are the result of metabolic dysregulation, and a compensatory increase in energy transduction that is inversely related. In cancer, the compensatory metabolic effect is the upregulation of glycolysis-the Warburg effect; in AD, a bioenergetic model based on the interaction between astrocytes and neurons indicates that the compensatory metabolic alteration is the upregulation of oxidative phosphorylation-an inverse Warburg effect. These two modes of metabolic alteration could contribute to an inverse relation between the incidence of the two diseases. We invoke this bioenergetic mechanism to furnish a molecular basis for an epidemiological observation, namely the incidence of sporadic forms of cancer and AD is inversely related. We furthermore exploit the molecular mechanisms underlying the diseases to propose common therapeutic strategies for cancer and AD based on metabolic intervention.

PMID: 23427097


PMCID: PMC3627084
 [Available on 2014/5/6]

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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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Curator: Aviva Lev-Ari, PhD, RN

Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease–like pathology and cognitive decline

  1. These authors contributed equally to this work.

    • Johannes vom Berg &
    • Stefan Prokop


  1. Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.

    • Johannes vom Berg,
    • Florian Mair &
    • Burkhard Becher
  2. Department of Neuropathology, Charité–Universitätsmedizin Berlin, Berlin, Germany.

    • Stefan Prokop,
    • Kelly R Miller,
    • Juliane Obst,
    • Roland E Kälin,
    • Ileana Lopategui-Cabezas,
    • Anja Wegner,
    • Carola G Schipke &
    • Frank L Heppner
  3. Department of Psychiatry, Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.

    • Carola G Schipke &
    • Oliver Peters
  4. Cognitive Neurobiology and Berlin Mouse Clinic for Neurology and Psychiatry, Humboldt University, Berlin, Germany.

    • York Winter
  5. Present address: Institute of Basic and Preclinical Sciences ‘Victoria de Girón’, Medical University of Havana, Havana, Cuba.

    • Ileana Lopategui-Cabezas
  6. These authors jointly directed this work.
    • Burkhard Becher &
    • Frank L Heppner



The pathology of Alzheimer’s disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (). Using theAPPPS1 Alzheimer’s disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer’s disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer’s disease pathology and cognitive deficits.

Nature Medicine 18, 1812–1819 (2012) doi:10.1038/nm.2965, Published online 25 November 2012

Psoriasis Drug Fights Alzheimer’s By Treating It Like An Auto-Immune Disease


In a study published this week in the journal Nature Medicine, Swedish and German researchers say a medication already widely in use to treat plaque psoriasis was able to slow the accumuation of amyloid plaques in the brains of mice, as well as improve brain functioning in older mice that already had Alzheimer’s disease.

The drug, ustekinumab, works by suppressing the brain’s immune response to the amyloid-beta protein. Its effectiveness lends support to the idea of Alzheimer’s disease as an auto-immune disease similar to type-2 diabetes, spurred at least in part by the bodies response to inflammation.

The study authors urged the U.S. Food & Drug Administration should approve ustekinumab for patients with early Alzheimer’s disease or mild cognitive impairment and said drugs that shut down specific immune responses — like those used in psoriasis, Crohn’s disease and multiple sclerosis — are “the ideal candidate for the initiation of clinical trials” for Alzheimer’s.

That’s very good news, because pharmaceutical companies have been ready to give up on Alzheimer’s drug development after so many of the drugs being tested for the past decade or more have been failures. Most of those drugs worked under different theories of treating Alzheimer’s disease, focusing more on things like busting up existing plaques or treating the external symptoms of Alzheimer’s.

Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

W. Sue T. Griffin, Ph.D.

N Engl J Med 2013; 368:770-771 February 21, 2013, DOI: 10.1056/NEJMcibr1214546

Immune events may influence development and progression of Alzheimer’s disease. In a mouse model, mice depleted of p40, a cytokine subunit, showed reduced cerebral amyloidosis. Administration of anti-p40 antibodies reduced levels of soluble β-amyloid and restored some cognitive function.

Neuroinflammation, expressed as frank microglial activation with excessive expression of immune cytokines, is fast acquiring the status of “principal culprit” in the unresolved connection between an elevated risk for the development of

  • sporadic Alzheimer’s disease and
  • traumatic brain injury,
  • systemic infections,
  • normal aging, and
  • several neurologic disorders.

Neuroinflammation also appears to be a substantial contributor to Alzheimer’s disease in persons with Down’s syndrome (owing to the excess gene dosage that is characteristic of the syndrome) and in persons with genetic mutations that affect the amyloid precursor protein (APP) or presenilin.1 The molecules and pathways that mediate the inflammation associated with Alzheimer’s disease have recently come under scrutiny. An advance in this area has been described by Vom Berg et al.,2 who used a mouse model of Alzheimer’s disease to investigate the role of proinflammatory cytokines in disease pathogenesis.

Their results show that damping the expression and signaling of the cytokines interleukin-12 and interleukin-23 in the mouse model is associated with decreases in microglial activation, in the level of soluble β-amyloid (Aβ), and in the overall Aβ plaque burden. These findings are consistent with earlier studies that linked microglial activation with excess expression of interleukin-1 (which regulates interleukin-12–interleukin-23 signaling3) and expression of APP (which when cleaved generates Aβ), the development of Aβ plaques, and the activation of microglia in the brains of patients with Alzheimer’s disease.

Vom Berg et al. also observed that intracerebroventricular delivery of an antibody against p40 — a subunit common to both interleukin-12 and interleukin-23 — reversed the age-related cognitive decline in mice and that this reversal was accompanied by a reduction in levels of soluble Aβ. These observations suggest that the suppression of signaling by interleukin-12, interleukin- 23, or other inflammatory cytokines may prevent or delay the onset of Alzheimer’s disease and, for patients already undergoing the cognitive decline of Alzheimer’s disease, may halt such decline. 

These findings raise the question of whether monoclonal p40 antibodies (ustekinumab and briakinumab), which have already been approved by the Food and Drug Administration for the treatment of psoriasis, should be tested in randomized, controlled trials for the treatment of Alzheimer’s disease. Also of interest is a large epidemiologic study4 in which the rate of incident Alzheimer’s disease decreased by almost 50% among persons who took the common nonsteroidal antiinflammatory agent (NSAID) ibuprofen for 5 years, a finding that suggests that experimental investigation of NSAIDs as preventive agents is warranted.

Given the mounting sociological, economic, and personal costs of Alzheimer’s disease, the lack of a perfect understanding of its mechanisms should not stop researchers from conducting clinical studies of a variety of strategies intended to reduce the risk of development of the disease and of experimental approaches to expedite its treatment.

W. Sue T. Griffin, Ph.D.: Disclosure forms provided by the author are available with the full text of this article at From the Donald W. Reynolds Department of Geriatrics and Institute on Aging, University of Arkansas for Medical Sciences, and the Geriatric Research, Education, and Clinical Center (GRECC) at the Central Arkansas Veterans Healthcare System — both in Little Rock.

1. Griffin WS, Barger SW. Neuroinflammatory cytokines — the common thread in Alzheimer’s pathogenesis. US Neurol 2010; 6(2):19-27.

2. Vom Berg J, Prokop S, Miller KR, et al. Inhibition of IL-12/ IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 2012;18:1812-9.

3. Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000;13: 715-25.

4. Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 2008;70:1672-7.

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Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

Reporter and writer: Larry H Bernstein, MD, FCAP

There has been an considerable success in the current state of expanding our knowledge in genomics and therapeutic targets in cancer (although clinical remission targets and relapse are a concern), cardiovascular disease, and infectious disease.  Our knowledge of  prenatal and perinatal events is still at an early stage.  The neurology front is by no means unattended.  Here there are two prominent drivers of progress –

  • genomic control of cellular apoptosis by ubiquitin pathways, and
  • epigenetic investigations,

among a complex sea of sequence-changes.  I indicate some of the current status in this.  However, as much as we have know, there is an incredible barrier to formulate working models because:

  1. ligand binding between DNA short-sequences is not predictable over time
  2. binding between proteins and DNA is still largely unknown
  3. specific regulatory roles between nucleotide-sequences and histone proeins are still unclear
  4. the relationship between intracellular as well as extracellular cations and the equilibria between cations and anions in intertitial fluid that bathes the cell and between organelles is virgin territory

Consequently, it is quite an accomplishment to have come as far as we have come, and yet, even with the huge compuational power at our disposal, there is insuficient data to unravel the complexity.  This may be especially true in the pathway to understanding of neurological and behavioral disorders.

Broad Map of Brain

John Markoff reports in the Feb 18 front-page of New York Times (Project would construct a broad map of the brain) that the Obama administration envisions a decade-long effort to examine the workings of the human brain and construct a map, comparable to what the Human Genome Project did for genetics.  It will be a collaboration between universities, the federal government, private foundations, and teams of scientists (neuro-, nano- and whoever else).  The goal is to break through the barrier to understanding the brain’s billions of neurons and gain greater insight into

  • perception
  • actions
  • and consciousness.

Essentially, it holds great promise for understanding

Alzheimer’s disease and Parkinson’s, as well as finding therapies for a variety of mental illnesses.  An open-ended question is whether it will also advance artificial intelligence research.  It is termed the Brain Activity Map project.

Schizophrenia Genomics

Scientists Reveal Genomic Explanation for Schizophrenia

July 11, 2011 Sequences Reveal Role for De Novo Mutations in Schizophrenia/
ttp:// Sequences Reveal Role for De Novo Mutations in Schizophrenia/ integrates diverse neurological signals that control the development of embryonic stem cell and neural progenitor cells/

Buffalo, NY (Scicast) (GenomeWeb News) –

Two new studies, published in Schizophrenia Research and in Nature Genetics, propose hypotheses in a new mouse model of schizophrenia that demonstrates how gestational brain changes cause behavioural problems later in life.  

The first study implicates

A fibroblast growth factor receptor protein, (FGFR1), targets diverse genes implicated in schizophrenia.  The research demonstrates how defects in an important neurological pathway in early development

  • may be responsible for the onset of schizophrenia later in life.

Individuals with sporadic schizophrenia tend to carry more deleterious genetic changes than found in the general population, according to an exome sequencing study  that appeared online in Nature Genetics yesterday.  “The occurrence of de novo mutations may in part explain the high worldwide incidence of schizophrenia,”  according to co-senior author Guy Rouleau, CHU Sainte-Justine Research Center of University of Montreal.
Researchers from Canada and France did exome sequencing on individuals from 14 parent-child trios, each comprised of an individual with schizophrenia and his or her unaffected parents. In the process, they found

  • 15 de novo mutations in coding sequences from eight individuals with the psychiatric condition, including
  • four nonsense mutations predicted to abbreviate protein sequences.

“They surmise that [de novo mutations] may account for some of the heritability reported for schizophrenia.  Recent exome sequencing studies involving parent-child trios have implicated de novo mutations in other brain-related conditions, including

  • autism spectrum disorder and
  • mental retardation.

To detect de novo genetic changes specific to schizophrenia, the team compared coding sequences from affected individuals with

  • the human reference genome, with
  • both of his or her parents, and
  • with 26 unrelated control individuals.

Of the 15 de-novo mutations verified by Sager sequencing,

  • 11 were missense mutations predicted to alter the amino acid sequence of the resulting protein and
  • four were nonsense mutations predicted to truncate it.

Among the genes containing nonsense mutations were the zinc finger protein-coding gene ZNF480, the karyopherin alpha 1 gene KPNA1, the low-density lipoprotein receptor-related gene LRP1, and the ALS-like protein-coding gene ALS2CL.

The 15 mutations were found in coding sequences from eight of the individuals with schizophrenia,

  • hinting at a higher de novo mutation rate in individuals with sporadic schizophrenia than is predicted in the population overall.

This difference seems to be specific to exomes, and the researchers noted that

  • de novo mutation rates across the entire genome are likely comparable in those with or without schizophrenia.

They conclude that the enrichment of [de novo mutations] within the coding sequence of individuals with schizophrenia may underlie the pathogenesis of many of these individual.  Most of the genes identified in this study have not been previously linked to schizophrenia, thereby providing new potential therapeutic targets.

The second study

  • identifies the Integrative Nuclear FGFR 1 Signaling (INFS) as a central intersection point for multiple pathways of
  • as many as 160 different genes believed to be involved in the disorder.

The lead author Dr. Michal Stachowiakthis (UB School of Medicine and Biomedical Sciences) suggests this  is the first model that explains schizophrenia

  1. from genes
  2. to development
  3. to brain structure and
  4. finally to behaviour .

A key challenge has been that patients with schizophrenia exhibit mutations in different genes. It is  possible to have 100 patients with schizophrenia and each one has a different genetic mutation that causes the disorder. The explanation is possibly because INFS integrates diverse neurological signals that control the development of embryonic stem cell and neural progenitor cells, and

  • links pathways involving schizophrenia-linked genes.

“INFS functions like the conductor of an orchestra,” explains Stachowiak. “It doesn’t matter which musician is playing the wrong note,

  • it brings down the conductor and the whole orchestra.

With INFS, we propose that

  • when there is an alteration or mutation in a single schizophrenia-linked gene,
  • the INFS system that controls development of the whole brain becomes untuned.

Using embryonic stem cells, Stachowiak and colleagues at UB and other institutions found that

  • some of the genes implicated in schizophrenia bind the FGFR1 (fibroblast growth factor receptor) protein,
  • which in turn, has a cascading effect on the entire INFS.

“We believe that FGFR1 is the conductor that physically interacts with all genes that affect schizophrenia,” he says. “We think that schizophrenia occurs

  • when there is a malfunction in the transition from stem cell to neuron, particularly with dopamine neurons.”

The researchers tested their hypothesis by creating an FGFR1 mutation in mice, which produced the hallmarks of the human disease: altered brain anatomy,

  • behavioural impacts and
  • overloaded sensory processes.

The researchers would like to devise ways to arrest development of the disease before it presents fully in adolescence or adulthood. The UB work adds to existing evidence that nicotinic agonists, might  help improve cognitive function in schizophrenics by acting on the INFS.


childhood-schizophrenia-symptoms (Photo credit: Life Mental Health)

English: Types of point mutations. With examples.

English: Types of point mutations. With examples. (Photo credit: Wikipedia)

Parkinson’s Disease


PINK1 and Parkin and Parkinson’s Disease

Studies of the familial Parkinson disease-related proteins PINK1 and Parkin have demonstrated that these factors promote the fragmentation and turnover of mitochondria following treatment of cultured cells with mitochondrial depolarizing agents. Whether PINK1 or Parkin influence mitochondrial quality control under normal physiological conditions in dopaminergic neurons, a principal cell type that degenerates in Parkinson disease, remains unclear. To address this matter, we developed a method to purify and characterize neural subtypes of interest from the adult Drosophila brain.

Using this method, we find that dopaminergic neurons from Drosophila parkin mutants accumulate enlarged, depolarized mitochondria, and that genetic perturbations that promote mitochondrial fragmentation and turnover rescue the mitochondrial depolarization and neurodegenerative phenotypes of parkin mutants. In contrast, cholinergic neurons from parkin mutants accumulate enlarged depolarized mitochondria to a lesser extent than dopaminergic neurons, suggesting that a higher rate of mitochondrial damage, or a deficiency in alternative mechanisms to repair or eliminate damaged mitochondria explains the selective vulnerability of dopaminergic neurons in Parkinson disease.

Our study validates key tenets of the model that PINK1 and Parkin promote the fragmentation and turnover of depolarized mitochondria in dopaminergic neurons. Moreover, our neural purification method provides a foundation to further explore the pathogenesis of Parkinson disease, and to address other neurobiological questions requiring the analysis of defined neural cell types.

Burmana JL, Yua S, Poole AC, Decala RB , Pallanck L. Analysis of neural subtypes reveals selective mitochondrial dysfunction in dopaminergic neurons from parkin mutants.

http://Burmana JL, Yua S, Poole AC, Decala RB , Pallanck L. Analysis of neural subtypes reveals selective mitochondrial dysfunction in dopaminergic neurons from parkin mutants./

Autophagy in Parkinson’s Disease.

Parkinson’s disease is a common neurodegenerative disease in the elderly. To explore the specific role of autophagy and the ubiquitin-proteasome pathway in apoptosis,

  • a specific proteasome inhibitor and macroautophagy inhibitor and stimulator were selected to investigate
  1. pheochromocytoma (PC12) cell lines
  2. transfected with human mutant (A30P) and wildtype (WT) -synuclein.
  • The apoptosis ratio was assessed by flow cytometry.
  • LC3heat shock protein 70 (hsp70) and caspase-3 expression in cell culture were determined by Western blot.
  • The hallmarks of apoptosis and autophagy were assessed with transmission electron microscopy.

Compared to the control group or the rapamycin (autophagy stimulator) group, the apoptosis ratio in A30P and WT cells was significantly higher after treatment with inhibitors of the proteasome and macroautophagy.

  1. The results of Western blots for caspase-3 expression were similar to those of flow cytometry;
  2. hsp70 protein was significantly higher in the proteasome inhibitor group than in control, but
  3. in the autophagy inhibitor and stimulator groups, hsp70 was similar to control.

These findings show that

  1. inhibition of the proteasome and autophagy promotes apoptosis, and
  2. the macroautophagy stimulator rapamycin reduces the apoptosis ratio.
  3. And inhibiting or stimulating autophagy has less impact on hsp70 than the proteasome pathway.

In conclusion,

  • either stimulation or inhibition of macroautophagy, has less impact on hsp70 than on the proteasome pathway.
  • rapamycin decreased apoptotic cells in A30P cells independent of caspase-3 activity.

Although several lines of evidence recently demonstrated crosstalk between autophagy and caspase-independent apoptosis, we could not confirm that

  • autophagy activation protects cells from caspase-independent cell death.

Undoubtedly, there are multiple connections between the apoptotic and autophagic processes. Inhibition of autophagy may

  • subvert the capacity of cells to remove
  • damaged organelles or to remove misfolded proteins, which
  • would favor apoptosis.

However, proteasome inhibition activated macroautophagy and accelerated apoptosis. A likely explanation is inhibition of the proteasome favors oxidative reactions that trigger apoptosis, presumably through

  • a direct effect on mitochondria, and
  • the absence of NADPH2 and ATP which may
  • deinhibit the activation of caspase-2 or MOMP.

Another possibility is that aggregated proteins induced by proteasome inhibition increase apoptosis.

Yang F, Yanga YP, Maoa CJ, Caoa BY, et al. Role of autophagy and proteasome degradation pathways in apoptosis of PC12 cells overexpressing human -synuclein. Neuroscience Letters 2009; 454:203–208. doi:10.1016/j.neulet.2009.03.027. Role_of_autophagy_and_proteasome_degradation_pathways_in_apoptosis_of_PC12_cells_overexpressing_human –synuclein/

Parkin-dependent Ubiquitination of Endogenous Bax

Autosomal recessive loss-of-function mutations within the PARK2 gene functionally inactivate the E3 ubiquitin ligase parkin, resulting

  • in neurodegeneration of catecholaminergic neurons and a familial form of Parkinson disease.

Current evidence suggests both

  • a mitochondrial function for parkin and
  • a neuroprotective role, which may in fact be interrelated.

The antiapoptotic effects of Parkin have been widely reported, and may involve

fundamental changes in the threshold for apoptotic cytochrome c release, but the substrate(s) involved in Parkin dependent protection had not been identified. This study demonstrates

  • the Parkin-dependent ubiquitination of endogenous Bax
  • comparing primary cultured neurons from WT and Parkin KO mice and
  • using multiple Parkin-overexpressing cell culture systems.

The direct ubiquitination of purified Bax was also observed in vitro following incubation with recombinant parkin.

  1. Parkin prevented basal and apoptotic stress induced translocation of Bax to the mitochondria.
  2. an engineered ubiquitination-resistant form of Bax retained its apoptotic function,
  3. but Bax KO cells complemented with lysine-mutant Bax
  • did not manifest the antiapoptotic effects of Parkin that were observed in cells expressing WT Bax.

The conclusion is that Bax is the primary substrate responsible for the antiapoptotic effects of Parkin, and provides mechanistic insight into at least a subset of the mitochondrial effects of Parkin.

Johnson BN, Berger AK, Cortese GP, and LaVoie MJ. The ubiquitin E3 ligase Parkin regulates the proapoptotic function of Bax. PNAS 2012, pp 6.
http:// The_ubiquitin_E3_ligase_Parkin_regulates_the_proapoptotic_function_of_Bax

                                                                                                                           nature10774-f3.2   ubiquitin structures  Rn1  Rn2

Ubiquitin is a small, compact protein characterized by a b-grasp fold.

Parkin Promotes Mitochondrial Loss in Autophagy

Parkin, an E3 ubiquitin ligase implicated in Parkinson’s disease,

  • promotes degradation of dysfunctional mitochondria by autophagy.

upon translocation to mitochondria, Parkin activates the ubiquitin–proteasome system (UPS) for

  • widespread degradation of outer membrane proteins.

We observe

  1. an increase in K48-linked polyubiquitin on mitochondria,
  2. recruitment of the 26S proteasome and
  3. rapid degradation of multiple outer membrane proteins.

The degradation of proteins by the UPS occurs independently of the autophagy pathway, and

  • inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in HeLa, SH-SY5Y and mouse cells.

Although the mitofusins Mfn1 and Mfn2 are rapid degradation targets of Parkin, degradation of additional targets is essential for mitophagy.

It appears that remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and reveal

  • a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates.

Chan NC, Salazar AM, Pham AH, Sweredoski MJ, et al. Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy. Human Molecular Genetics 2011; 20(9): 1726–1737. doi:10.1093/hmg/ddr048. Broad_activation_of_the_ubiquitin–proteasome_system_by_Parkin_is_critical_for_mitophagy/

Autophagy impairment: a crossroad

Nassif M and Hetz C.  Autophagy impairment: a crossroad between neurodegeneration and tauopathies.  BMC Biology 2012; 10:78. impairment: a crossroad between neurodegeneration and tauopathies/
Molecular Neurodegeneration/Nassif M and Hetz C/

Impairment of protein degradation pathways such as autophagy is emerging as

  • a consistent and transversal pathological phenomenon in neurodegenerative diseases, including Alzheimer´s, Huntington´s, and Parkinson´s disease.

Genetic inactivation of autophagy in mice has demonstrated a key role of the pathway in maintaining protein homeostasis in the brain,

  • triggering massive neuronal loss and
  • the accumulation of abnormal protein inclusions.

This paper in Molecular Neurodegeneration from Abeliovich´s group now suggests a role for

  • phosphorylation of Tau and
  • the activation of glycogen synthase kinase 3β (GSK3β)
  • in driving neurodegeneration in autophagy-deficient neurons.

This study illuminatess the factors driving neurofibrillary tangle formation in Alzheimer´s disease and tauopathies.

autophagy & apoptosis          stem cell reprogramming     lysosomes.jpeg   exosomes.jpeg   Epigenetics

images: autophagy, stem cell remodeling, lysosome, exosome, epigenetics,

Alzheimer’s Disease

Alzheimer’s Linked To Rare Gene Mutation That Affects Immune System

Article Date: 15 Nov 2012 –
Two international studies published this week point to a link between Alzheimer’s disease and a rare gene mutation that affects the immune system’s inflammation response. The discovery supports an emerging theory about the role of the immune system in the development of Alzheimer’s disease.  Both studies were published online this week in the New England Journal of Medicine, one led by John Hardy of University College London, and the other led by the Iceland-based global company deCode Genetics.
Alzheimer’s is a form of distressing brain-wasting disease that gradually robs people of their memories and their ability to lead independent lives. Its main characteristic is the build up of
  • protein tangles and
  • plaques inside and between brain cells, which eventually
  • disrupts their ability to communicate with each other.
Both teams conclude that a rare mutation in a gene called TREM2, which helps trigger immune system responses, raises the risk for developing Alzheimer’s disease. One study suggests it raises it three-fold, the other, four-fold.  The UCL-led study included researchers from 44 institutions around the world and data on a total of 25,000 people.
After homing in on the TREM2 gene using new sequencing techniques, they carried out further sequencing that identified a set of
  • rare mutations that occurred more often in 1,092 Alzheimer’s disease patients than in a group of 1,107 healthy controls.
They evaluated the most common mutation, R47H, and confirmed that this variant of TREM2 substantially increases the risk for Alzheimer’s disease.  R47H mutation was present in 1.9 percent of the Alzheimer’s patients and in only 0.37 percent of the controls.  The researchers on the study led by deCode Genetics indicate that this strong effect is on a par with that of the well-established gene variant known as APOE4. Not all people who have  the R47H variant will develop Alzheimer’s and in those who do, other genes and environmental factors will also play a role — but like APOE 4 it does substantially increase risk,” Carrasquillo explains.
The study led by deCode Genetics involved collaborators from Iceland, Holland, Germany and the US, not only found a strong link between the R47H variant and Alzheimer’s disease, but the variant also

  • predicts poorer cognitive function in older people without Alzheimer’s.
 In a statement, lead author Kari Stefánsson, CEO and co-founder of deCODE Genetics says:
The discovery of variant TREM2 is important because
  • it confers high risk for Alzheimer’s and
  • because the gene’s normal biological function has been shown to reduce immune response
 He surmises that the  combined factors make TREM2 an attractive target for drug development.
Using deCode’s genome sequencing and genotyping technology, Stefánsson and colleagues identified
  • approximately 41 million markers, including 191,777 functional variants, from
  • 2,261 Icelandic samples.
They further analyzed these variants against the genomes of
  • 3,550 people with Alzheimer’s disease and
  • a control group of over-85s who did not have a diagnosis of Alzheimer’s.
This led to them finding the TREM2 variant, and to make sure this was not just a feature of Icelandic people,
  • they replicated the findings against other control populations in the United States, Germany, the Netherlands and Norway.
Stefánsson says that the results were enabled by having
  • sophisticated research tools,
  • access to expanded and high quality genomic data sets, and
  • investigators with profound analytic skills,
Researching into genetic causes of disease can, thereby,  be carried out using an approach that combines sequence data and biological knowledge to find new drug targets.

R47H Variant of TREM2 and Immune Response

 Preclinical studies have found that
  • TREM2 is important for clearing away cell debris and amyloid protein, the protein that is associated with the brain plaques
  • that are characteristic of Alzheimer’s disease.
 The gene helps control the
  • inflammation response associated with Alzheimer’s and cognitive decline.
Rosa Rademakers, a co-author in the UCL-led study, runs a lab at the Mayo Clinic in Florida that helped to pinpoint the R47H variant of TREM2.  Other studies also link the immune system to Alzheimer’s disease, but
  • studies are needed to establish that R47H  acts by altering immune function.


12/10/12 · Emily Humphreys
Epigenetic effects were first described by Conrad Waddington in 1942 as phenotypic changes resulting from an organism interacting with its environment.1 Today, epigenetics is
  • heritable effects in gene expression that are
  • not based on the genetic sequence.
One known epigenetic mechanism includes posttranslational modifications of histones that are
  • found in the nuclei of nearly all eukaryotes and
  • function to package DNA into nucleosomes.
Histone proteins can be heavily decorated with posttranslational modifications (PTMs), such as
  • acetyl-,
  • methyl-, and
  • phosphoryl- groups at distinct amino acid residues.
These modifications are mainly
  • located in the N-terminal tails of the histone and
  • protrude from the core nucleosome structure.
Gene regulation, and the downstream epigenetic effects, can also
  • depend on the cis or trans orientation of the PTMs.2
One PTM, acetylation, is an important determinant of cell replication, differentiation, and death.3  Zhang, et al. investigated the acetylation of histone proteins in Alzheimer’s disease (AD) pathology found in postmortem human brain tissue compared to neurological controls. To study histone acetylation,
  • histones were isolated from frozen temporal lobe samples of patients with advanced AD.
Histones were quantified using Selected-reaction-monitoring (SRM)-based targeted proteomics, an LC-MS/MS-based technique demonstrated by the Zhang lab.4  Histones were also analyzed using western blot analysis and LC-MS/MS-TMT (tandem-mass-tagging) quantitative proteomics. The results of these three experimental strategies agreed, further validating the specificity and sensitivity of the targeted proteomics methods. Histone acetylation was  reduced throughout in the AD temporal lobe compared to matched controls.
  • the histone H3 K18/K23 acetylation was significantly reduced.
Alzheimer’s disease and aging have also been associated with loss of histone acetylation in mouse model studies.5 In addition, Francis et al. found
  • cognitively impaired mice had a 50% reduced H4 acetylation in APP/PS1 mice than wild-type littermates.6
In mice, histone deacetylase inhibitors heve restored histone acetylation and improved memory in mice with age-related impairments or in models for other neurodegenerative diseases.7
Further studies of histone acetylation in AD could lead to target therapies in the disease pathology of neurodegenerative diseases, and
  • increase our understanding of how epigenetic mechanisms, such as histone acetylation, alter gene regulation.
1. Waddington, C.H., (1942). ‘The epigenotype‘, Endeavour, 1942 (1), (pp. 18-20)
2. Sidoli, S., Cheng, L., and Jensen O.N. (2012) ‘Proteomics in chromatin biology and epigenetics: Elucidation of post-translational modifications of histone proteins by mass spectrometry‘, Journal of Proteomics, 75 (12), (pp. 3419-3433)
3. Zhang. K., et al. (2012) ‘Targeted proteomics for quantification of histone acetylation in Alzheimer’s disease‘, Proteomics, 12 (8), (pp. 1261-1268)
4. Darwanto, A., et al., (2010) ‘A modified “cross-talk” between histone H2B Lys-120 ubiquitination and H3 Lys-K79 methylation‘, The Journal of Biological Chemistry, 285 (28), (pp. 21868-21876)
5. Govindarajan, N., et al. (2011) ‘Sodium butyrate improves memory function in an Alzheimer’s disease model when administered at an advanced stage of disease progression‘, Journal of Alzheimer’s Disease, 26 (1), (pp.187-197)
6. Francis, Y.I., et al., (2009) ‘Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer’s disease‘, Journal of Alzheimer’s Disease, 18 (1), (pp. 131-139)
7. Kilgore, M., et al., (2010) ‘Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease‘, Neuropsychopharmacology, 35 (4), (pp. 870-880)
Tags: acetylation, alzheimers disease, epigenetics, histone, targeted proteomics

Tau amyloid

An Outcast Among Peers Gains Traction on Alzheimer’s Cure

Gareth Phillips for The Wall Street Journal
 November 10, 2012, on page A1 in the U.S. edition of The Wall Street Journal
After years of effort, researcher Dr. Claude Wischik is awaiting the results of new clinical trials that will test his theory on the cause of Alzheimer’s.
Dr. Wischik, an Australian in his early 30s in the 1980s, was attempting to answer a riddle: What causes Alzheimer’s disease? He needed to examine brain tissue from Alzheimer’s patients soon after death, which required getting family approvals and enlisting mortuary technicians to extract the brains. He collected more than 300 over about a dozen years.
Alzheimer’s researcher Claude Wischik had a view that a brain protein called tau-not plaque is largely responsible. WSJ’s Shirley Wang spoke with Dr. Wischik about his work on a new drug to treat the devastating disease.
The 63-year-old researcher believes that a protein called tau
  • forms twisted fibers known as tangles inside the brain cells of Alzheimer’s patients and is largely responsible for driving the disease.
For 20 years, billions of dollars of pharmaceutical investment has placed chief blame on a different protein, beta amyloid, which
  • forms sticky plaques in the brains of sufferers.
A string of experimental drugs designed to attack beta amyloid have failed recently in clinical trials.

Wherefore Tau thy go?

Dr. Wischik, who now lives in Scotland, sees this as tau’s big moment. The company he co-founded 10 years ago, TauRx Pharmaceuticals Ltd., has developed an experimental Alzheimer’s drug that it will begin testing in the coming weeks in two large clinical trials. Other companies are also investing in tau research. Roche Holding bought the rights to a type of experimental tau drug from Switzerland’s closely held AC Immune SA.

Wischik is a scientist who has struggled against a prevailing orthodoxy. In 1854, British doctor John Snow traced a cholera outbreak in London to a contaminated water supply, but his discovery was rejected. A very infamous example is the discovery of the cause of child-bed fever in Rokitanski’s University of Vienna by Ignaz Semmelweis. In 1982, two Australian scientists declared that bacteria (H. pylori) caused peptic ulcers, later to be awarded the 2005 Nobel Prize in medicine for their discovery.
Dr. Wischik says he and other tau-focused scientists have been shouted down over the years by what he calls the “amyloid orthodoxy.”  But Dr. Wischik has been hampered by inconclusive research. A small clinical trial of TauRx’s drug in 2008 produced  mixed, results. Of course, influential scientists still think that beta amyloid plays a central role. Although Roche is investing in tau, Richard Scheller, head of drug research at Roche’s biotech unit, Genentech, says the company still has a strong interest in beta amyloid (hedging the bet).  He thinks amyloid drugs may have better results if  testing on Alzheimer’s patients occurs much earlier in the disease to prove effective; Roche recently announced plans to conduct such a trial.  Simply put -“Drugs tied to conventional theories on Alzheimer’s causes haven’t so far been effective.” Scientists Dr. Wischik accuses of wrongly fixating on beta amyloid argue that the evidence for pursuing amyloid is strong. One view expressed is that drugs to attack both beta amyloid and tau will be necessary.
Alzheimer’s disease is the leading cause of dementia in the elderly, and according to the World Health Organization, the cost of caring for dementia sufferers totals about $600 billion each year world-wide. The disease was first identified in 1906 by German physician Alois Alzheimer, who found in the brain of a deceased woman who had suffered from dementia the plaques and tangles that riddled the tissue. In the 1960s, Dr. Martin Roth and colleagues showed that
  • the degree of clinical dementia was worse for patients with more tangles in the brain.
In the 1980s, Dr. Wischik joined Dr. Roth’s research group at Cambridge University as a Ph.D student, and was quickly assigned the task of
  • determining what tangles were made of, which launched his brain-collecting mission, and years of examining tissue.
Finally, in 1988, he and colleagues at Cambridge published a paper demonstrating for the first time that
  • the tangles first observed by Alzheimer were made at least in part of the protein tau, which was supported by later research.
Like all of the body’s proteins, tau has a normal, helpful function—working inside neurons to help
  • stabilize the fibers that connect nerve cells.
When it misfires, tau clumps together to form harmful tangles that kill brain cells.
Dr. Wischik’s discovery was important news in the Alzheimer’s field:
  • identifying the makeup of tangles made it possible to start developing ways to stop their formation. But by the early 1990s, tau was overtaken by another protein: beta amyloid.

Signs of Decline

Several pieces of evidence convinced an influential group of scientists that beta amyloid was the primary cause of Alzheimer’s.
  •  the discovery of several genetic mutations that all but guaranteed a person would develop a hereditary type of the disease.
  • these appeared to increase the production or accumulation of beta amyloid in the brain,
  • which led scientists to believe that amyloid deposits were the main cause of the disease.
 Athena Neurosciences, a biotech company whose founders included Harvard’s Dr. Selkoe, focused in earnest on developing drugs to attack amyloid. Meanwhile, tau researchers say they found it hard to get research funding or to publish papers in medical journals. It became difficult to have a good publication on tau, because the amyloid cascade was like a dogma. It became the case that if you were not working in the amyloid field you were not working on Alzheimer’s disease. Dr. Wischik and his colleagues fought to keep funding from the UK’s Medical Research Council for the repository of brain tissue they maintained at Cambridge, he says. The brain bank became an important tool. In the early 1990s, Dr. Wischik and his colleagues compared the postmortem brains of Alzheimer’s sufferers against those of people who had died without dementia, to see how their levels of amyloid and tau differed. They found that both healthy brains and Alzheimer’s brains could be filled with amyloid plaque, but only Alzheimer’s brains contained aggregated tau.
  • as the levels of aggregated tau in a brain increased, so did the severity of dementia.
In the mid-1990s, Dr. Wischik discovered that
  • a drug sometimes used to treat psychosis dissolved tangles
Nevertheless, American and British venture capitalists wanted to invest in amyloid projects, not tau.
By 2002, Dr. Wischik scraped together about $5 million from Asian investors with the help of a Singaporean physician who was the father of a classmate of Dr. Wischik’s son in Cambridge. TauRx is based in Singapore but conducts most of its research in Aberdeen, Scotland. As his tau effort launched, early tests of drugs designed to attack amyloid plaques were disappointing. To better understand these results, a team of British scientists largely unaffiliated with Athena or the failed clinical trial decided to examine the brains of patients who had participated in the study. They waited for the patients to die, and then, after probing the brains, concluded that
  • the vaccine had indeed cleared amyloid plaque but hadn’t prevented further neurodegeneration.

Peter Davies, an Alzheimer’s researcher at the Feinstein Institute for Medical Research in Manhasset, NY, recalls hearing a researcher at a conference in the early 2000s concede that his amyloid research results “don’t fit the hypothesis, but we’ll continue until they do! “I just sat there with my mouth open,” he recalls.

In 2004, TauRx began a clinical trial of its drug, called methylene blue, in 332 Alzheimer’s patients. Around the same time, a drug maker called Elan Corp., which had bought Athena Neurosciences, began a trial of an amyloid-targeted drug called bapineuzumab in 234 patients. A key moment came in 2008, when Dr. Wischik and Elan presented results of their studies at an Alzheimer’s conference in Chicago. The Elan drug
  • failed to improve cognition any better than a placebo pill, causing Elan shares to plummet by more than 60% over the next few days.
The TauRx results Dr. Wischik presented were more positive, though not unequivocal. The study showed that,
  • after 50 weeks of treatment, Alzheimer’s patients taking a placebo had fallen 7.8 points on a test of cognitive function,
  • while people taking 60 mg of TauRx’s drug three times a day had fallen one point—
  • translating into an 87% reduction in the rate of decline for people taking the TauRx drug.
But TauRx didn’t publish a full set of data from the trial, causing some skepticism among researchers. (Dr. Wischik says it didn’t to protect the company’s commercial interests). What’s more,
  • a higher, 100-mg dose of the drug didn’t produce the same positive effects in patients;
Dr. Wischik blames this on the way the 100-mg dose was formulated, and says the company is testing a tweaked version of the drug in its new clinical trials, which will begin enrolling patients late this year.
This summer, a trio of companies that now own the rights to bapineuzumab—Elan, Pfizer and Johnson & Johnson—
  • scrapped development of the drug after it failed to work in two large clinical trials.
Then in August, Eli Lilly & Co. said its experimental medicine targeting beta amyloid,
  • solanezumab, failed to slow the loss of memory or basic skills like bathing and dressing in two trials
  • involving 2,050 patients with mild or moderate Alzheimer’s.
Lilly has disclosed that in one of the trials, when moderate patients were stripped away,
  • the drug slowed cognitive decline only in patients with mild forms of the disease.
Still fervent believers assert that beta amyloid needs to be attacked very early in the disease cycle—
  • perhaps before symptoms begin.
This spring, the U.S. government said it would help fund a $100 million trial of Roche’s amyloid-targeted drug, crenezumab, in 300 people
  • who are genetically predisposed to develop early-onset Alzheimer’s but who don’t yet have symptoms.
This trial should help provide a “definitive” answer about the theory.
Scientists and investors are giving more attention to tau. Roche this year said it would pay Switzerland’s AC Immune an undisclosed upfront fee for the rights to a new type of tau-targeted drug, and up to CHF400 million in additional payments if any drugs make it to market.
Dr. Buee, the longtime tau researcher in France, says Johnson & Johnson asked him to provide advice on tau last year, and that he’s currently discussing a tau research contract with a big pharmaceutical company. (A Johnson & Johnson spokeswoman says the company invited Dr. Buee and other scientists to a meeting to discuss a range of approaches to fighting Alzheimer’s.)
With its new clinical trial program under way, TauRx is the first company to test a tau-targeted drug against Alzheimer’s in a large human study, known in the industry as a phase 3 trial.  Dr. Wischik

  • In the end…it’s down to the phase 3 trial.

Protein Degradation in Neurodegenerative Diseases

Cebollero E , Reggiori F  and Kraft C.  Ribophagy: Regulated Degradation of Protein Production Factories. Int J Cell Biol. 2012; 2012: 182834. doi:  10.1155/2012/182834 (online).

During autophagy, cytosol, protein aggregates, and organelles

  • are sequestered into double-membrane vesicles called autophagosomes and delivered to the lysosome/vacuole for breakdown and recycling of their basic components.

In all eukaryotes this pathway is important for

  • adaptation to stress conditions such as nutrient deprivation, as well as
  • to regulate intracellular homeostasis by adjusting organelle number and clearing damaged structures.

Starvation-induced autophagy has been viewed as a nonselective transport pathway; but recent studies have revealed that

  • autophagy is able to selectively engulf specific structures, ranging from proteins to entire organelles.

In this paper, we discuss recent findings on the mechanisms and physiological implications of two selective types of autophagy:

  • ribophagy, the specific degradation of ribosomes, and
  • reticulophagy, the selective elimination of portions of the ER.

Lee JH, Yu WH,…, Nixon RA.  Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations. Cell 2010; 141, 1146–1158. DOI 10.1016/j.cell.2010.05.008.

Macroautophagy is a lysosomal degradative pathway essential for neuron survival. Here, we show

  • that macroautophagy requires the Alzheimer’s disease (AD)-related protein presenilin-1 (PS1).

In PS1 null blastocysts, neurons from mice hypomorphic for PS1 or conditionally depleted of PS1,

  • substrate proteolysis and autophagosome clearance during macroautophagy are prevented
  • as a result of a selective impairment of autolysosome acidification and cathepsin activation.

These deficits are caused by failed PS1-dependent targeting of the v-ATPase V0a1 subunit to lysosomes. N-glycosylation of the V0a1 subunit,

  • essential for its efficient ER-to-lysosome delivery,
  • requires the selective binding of PS1 holoprotein to the unglycosylated subunit and the  sec61alpha/ oligosaccharyltransferase complex.

PS1 mutations causing early-onset AD produce a similar lysosomal/autophagy phenotype in fibroblasts from AD patients. PS1 is therefore essential for v-ATPase targeting to lysosomes, lysosome acidification, and proteolysis during autophagy. Defective lysosomal proteolysis represents a basis for pathogenic protein accumulations and neuronal cell death in AD and suggests previously unidentified therapeutic targets.

Hanai JI, Cao P, Tanksale P, Imamura S, et al. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. The Journal of Clinical Investigation  2007; 117(12):3930-3951.

Gene Wars Span Eons

Transposons have been barging into genomes and crossing species boundaries throughout evolution. Rapidly evolving bacterial species often use them to transmit antibiotic resistance to one another.  Nearly half of the DNA in the human genome consists of transposons, and the percentage can potentially creep upward with every generation. That’s because nearly 20 percent of transposons are capable of replicating in a way that is unconstrained by the normal rules of DNA replication during cell division ― although through generations over time, most have become inactivated and no longer pose a threat.

While humans are riddled with transposons, compared to some organisms, they’ve gotten off easy, according to Madhani, a professor of biochemistry and biophysics at UCSF. The water lily’s genome is 99 percent derived from transposons. The lowly salamander has about the same number of genes as humans, but in some species the genome is nearly 40 times bigger, due to all the inserted, replicating transposons.

The scientists’ discovery of SCANR and how it targets transposons in the yeast Cryptococcus neoformans builds upon the Nobel-Prize-winning discovery of jumping genes by maize geneticist Barbara McClintock, and the Nobel-prize-winning discovery by molecular biologists Richard Roberts and Phillip Sharp that parts of a single gene may be separated along chromosomes by intervening bits of DNA, called introns. Introns are transcribed into RNA from DNA but then are spliced out of the instructions for building proteins.

In the current study, the researchers discovered that the cell’s splicing machinery stalls when it gets to transposon introns. SCANR recognizes this glitch and

  • prevents transposon replication by
  • triggering the production of “small interfering RNA” molecules, which
  • neutralize the transposon RNA.

The earlier discovery by biologists Andrew Fire and Craig Mello of the phenomenon of RNA interference, a feature of this newly identified transposon targeting, also led to a Nobel Prize. “Scientists might find that many of the peculiar ways in which genes are expressed differently in higher organisms are, like

  • intron splicing in the case of SCANR, useful
  • in distinguishing and defending ‘self’ genes from ‘non-self’ genes,” Madhani said.

Researchers  at UCSF ( Phillip Dumesic, an MD/PhD student and first author of the study, graduate students Prashanthi Natarajan and Benjamin Schiller, and postdoctoral fellow Changbin Chen, PhD.) and collaborators at the Whitehead Institute of Medical Research in Cambridge, Mass., and from the Scripps Research Institute in La Jolla, Calif., contributed to the research.

Researchers Discover Gene Invaders Are Stymied by a Cell’s Genome Defense

If unrestrained, transposons replicate and insert themselves randomly throughout the genome.

San Francisco, CA  (Scicasts) – Gene wars rage inside our cells, with invading DNA regularly threatening to subvert our human blueprint. Now, building on Nobel-Prize-winning findings, UC San Francisco researchers have discovered a molecular machine that helps protect a cell’s genes against these DNA interlopers.

The machine, named SCANR, recognizes and targets foreign DNA. The UCSF team identified it in yeast, but comparable mechanisms might also be found in humans. The targets of SCANR are

  • small stretches of DNA called transposons, a name that conjures images of alien scourges.

But transposons are real, and to some newborns, life threatening. Found inside the genomes

  • of organisms as simple as bacteria and
  • as complex as humans,

they are in a way alien ― at some point,

  • each was imported into its host’s genome from another species.

Unlike an organism’s native genes, which are reproduced a single time during cell division, transposons ― also called jumping genes ― replicate multiple times, and

  • insert themselves at random places within the DNA of the host cell.

When transposons insert themselves in the middle of an important gene, they may cause malfunction, disease or birth defects.

But just as the immune system has ways of distinguishing what is part of the body and what is foreign and does not belong, researchers led by UCSF’s Dr. Hiten Madhani, discovered in

  • SCANR a novel way through which the genetic machinery within a cell’s nucleus recognizes and targets transposons.

“We’ve known that only a fraction of human-inherited diseases are caused by these mobile genetic elements,” Madhani said. “Now we’ve found that cells use a step in gene expression to distinguish ‘self’ from ‘non-self’ and to halt the spread of transposons.” The study was published online Feb. 13 in the journal Cell (

Epigenetics of brain and brawn

Study Shows Epigenetics Shapes Fate of Brain vs. Brawn Castes in Carpenter Ants

Philadelphia, PA (Scicasts) – The recently published genome sequences of seven well-studied ant species are opening up new vistas for biology and medicine.  A detailed look at molecular mechanisms that underlie the complex behavioural differences in two worker castes in the Florida carpenter ant, Camponotus floridanus, has revealed a link to epigenetics. This is the study of how the expression or suppression of particular genes by chemical modifications affects an organism’s

  • physical characteristics,
  • development, and
  • behaviour.

Epigenetic processes not only play a significant role in many diseases, but are also involved in longevity and aging. Interdisciplinary research teams led by Dr. Shelley Berger, from the Perelman School of Medicine at the University of Pennsylvania, in collaboration with teams led by Danny Reinberg from New York University and Juergen Liebig from Arizona State University, describe their work in Genome Research. The group found that epigenetic regulation is key to

  • distinguishing one caste, the “majors”, as brawny Amazons of the carpenter ant colony,
  • compared to the “minors”, their smaller, brainier sisters.

These two castes have the same genes, but strikingly distinct behaviours and shape.

Ants, as well as termites and some bees and wasps, are eusocial species that organize themselves into rigid caste-based societies, or colonies, in which only one queen and a small contingent of male ants are usually fertile and reproduce. The rest of a colony is composed of functionally sterile females that are divided into worker castes that perform specialized roles such as

  • foragers,
  • soldiers, and
  • caretakers.

In Camponotus floridanus, there are two worker castes that are physically and behaviourally different, yet genetically very similar.  “For all intents and purposes, those two castes are identical when it comes to their gene sequences,” notes senior author Berger, professor of Cell and Developmental Biology. “The two castes are a perfect situation to understand

  • how epigenetics,
  • how regulation ‘above’ genes,

plays a role in establishing these dramatic differences in a whole organism.”

To understand how caste differences arise, the team examined the role of modifications of histones throughout the genome. They produced the first genome-wide epigenetic maps of genome structure in a social insect. Histones can be altered by the addition of small chemical groups, which affect the expression of genes. Therefore, specific histone modifications can create dramatic differences between genetically similar individuals, such as the physical and behavioural differences between ant castes. “These chemical modifications of histones alter how compact the genome is in a certain region,” Simola explains. “Certain modifications allow DNA to open up more, and some of them to close DNA more. This, in turn, affects how genes get expressed, or turned on, to make proteins.

In examining several different histone modifications, the team found a number of distinct differences between the major and minor castes. Simola states that the most notable modification,

  • discriminates the two castes from each other and
  • correlates well with the expression levels of different genes between the castes.

And if you look at which genes are being expressed between these two castes, these genes correspond very nicely to the brainy versus brawny idea. In the majors we find that genes that are involved in muscle development are expressed at a higher level, whereas in the minors, many genes involved in brain development and neurotransmission are expressed at a higher level.”

These changes in histone modifications between ant castes are likely caused by a regulator gene, called CBP, that has “already been implicated in aspects of learning and behaviour by genetic studies in mice and in certain human diseases,” Berger says. “The idea is that the same CBP regulator and histone modification are involved in a learned behaviour in ants – foraging – mainly in the brainy minor caste, to establish a pattern of gene regulation that leads to neuronal patterning for figuring out where food is and being able to bring the food back to the nest.”  Simola notes that “we know from mouse studies that if you inactivate or delete the CBP regulator, it actually leads to significant learning deficits in addition to craniofacial muscular malformations.  So from mammalian studies, it’s clear this is an important protein involved in learning and memory.”

The research team is looking ahead to expand the work by manipulating the expression of the CBP regulator in ants to observe effects on caste development and behaviour. Berger observes that all of the genes known to be major epigenetic regulators in mammals are conserved in ants, which makes them a  good model for studying behaviour and longevity.

Research Reveals Mechanism of Epigenetic Reprogramming

Cambridge, UK (Scicasts) – New research reveals a potential way for how parents’ experiences could be passed to their offspring’s genes.

Epigenetics is a system that turns our genes on and off. The process works by chemical tags, known as epigenetic marks, attaching to DNA and telling a cell to either use or ignore a particular gene. The most common epigenetic mark is a methyl group.

  • When these groups fasten to DNA through a process called methylation
  • they block the attachment of proteins which normally turn the genes on.

As a result, the gene is turned off.

Scientists have witnessed epigenetic inheritance, the observation that offspring may inherit altered traits due to their parents’ past experiences. For example, historical incidences of famine have resulted in health effects on the children and grandchildren of individuals who had restricted diets,

  • possibly because of inheritance of altered epigenetic marks caused by a restricted diet.

However, it is thought that between each generation

  • the epigenetic marks are erased in cells called primordial gene cells (PGC), the precursors to sperm and eggs.

This ‘reprogramming’ allows all genes to be read afresh for each new person – leaving scientists to question how epigenetic inheritance could occur.

The new Cambridge study initially discovered how the DNA methylation marks are erased in PGCs. The methylation marks are converted to hydroxymethylation which is then

  • progressively diluted out as the cells divide.

This process turns out to be remarkably efficient and seems to reset the genes for each new generation.

The researchers,  also found that some rare methylation can ‘escape’ the reprogramming process and can thus be passed on to offspring – revealing how epigenetic inheritance could occur. This is important because aberrant methylation could accumulate at genes during a lifetime in response to environmental factors, such as chemical exposure or nutrition, and can cause abnormal use of genes, leading to disease. If these marks are then inherited by offspring, their genes could also be affected. The  research demonstrates how genes could retain some memory of their past experiences, indicating that the idea that epigenetic information is erased between generations – should be reassessed.  The precursors to sperm and eggs are very effective in erasing most methylation marks, but they are fallible and at a low frequency may allow some epigenetic information to be transmitted to subsequent generations.

Professor Azim Surani from the University of Cambridge, principal investigator of the research, said: “The new study has the potential to be exploited in two distinct ways.

  1. how to erase aberrant epigenetic marks that may underlie some diseases in adults.
  2. address whether germ cells can acquire new epigenetic marks through environmental or dietary influences on parents that may evade erasure and be transmitted to subsequent generations

The research was published 25 January, in the journal Science. Story adapted from the University of Cambridge.

Study Suggests Expanding the Genetic Alphabet May Be Easier than Previously Thought

Featured In: Academia News | Genomics

Monday, June 4, 2012

A new study led by scientists at The Scripps Research Institute suggests that the replication process for DNA—the genetic instructions for living organisms that is composed of four bases (C, G, A and T)—is more open to unnatural letters than had previously been thought. An expanded “DNA alphabet” could carry more information than natural DNA, potentially coding for a much wider range of molecules and enabling a variety of powerful applications, from precise molecular probes and nanomachines to useful new life forms.

The new study, which appears in the June 3, 2012 issue of Nature Chemical Biology, solves the mystery of how a previously identified pair of artificial DNA bases can go through the DNA replication process almost as efficiently as the four natural bases.

“We now know that the efficient replication of our unnatural base pair isn’t a fluke, and also that the replication process is more flexible than had been assumed,” said Floyd E. Romesberg, associate professor at Scripps Research, principal developer of the new DNA bases, and a senior author of the new study. The Romesberg laboratory collaborated on the new study with the laboratory of co-senior author Andreas Marx at the University of Konstanz in Germany, and the laboratory of Tammy J. Dwyer at the University of San Diego.

Adding to the DNA Alphabet

Romesberg and his lab have been trying to find a way to extend the DNA alphabet since the late 1990s. In 2008, they developed the efficiently replicating bases NaM and 5SICS, which come together as a complementary base pair within the DNA helix, much as, in normal DNA, the base adenine (A) pairs with thymine (T), and cytosine (C) pairs with guanine (G).

The following year, Romesberg and colleagues showed that NaM and 5SICS could be efficiently transcribed into RNA in the lab dish. But these bases’ success in mimicking the functionality of natural bases was a bit mysterious. They had been found simply by screening thousands of synthetic nucleotide-like molecules for the ones that were replicated most efficiently. And it had been clear immediately that their chemical structures lack the ability to form the hydrogen bonds that join natural base pairs in DNA. Such bonds had been thought to be an absolute requirement for successful DNA replication‑—a process in which a large enzyme, DNA polymerase, moves along a single, unwrapped DNA strand and stitches together the opposing strand, one complementary base at a time.

An early structural study of a very similar base pair in double-helix DNA added to Romesberg’s concerns. The data strongly suggested that NaM and 5SICS do not even approximate the edge-to-edge geometry of natural base pairs—termed the Watson-Crick geometry, after the co-discoverers of the DNA double-helix. Instead, they join in a looser, overlapping, “intercalated” fashion. “Their pairing resembles a ‘mispair,’ such as two identical bases together, which normally wouldn’t be recognized as a valid base pair by the DNA polymerase,” said Denis Malyshev, a graduate student in Romesberg’s lab who was lead author along with Karin Betz of Marx’s lab.

Yet in test after test, the NaM-5SICS pair was efficiently replicable. “We wondered whether we were somehow tricking the DNA polymerase into recognizing it,” said Romesberg. “I didn’t want to pursue the development of applications until we had a clearer picture of what was going on during replication.”

Edge to Edge

To get that clearer picture, Romesberg and his lab turned to Dwyer’s and Marx’s laboratories, which have expertise in finding the atomic structures of DNA in complex with DNA polymerase. Their structural data showed plainly that the NaM-5SICS pair maintain an abnormal, intercalated structure within double-helix DNA—but remarkably adopt the normal, edge-to-edge, “Watson-Crick” positioning when gripped by the polymerase during the crucial moments of DNA replication.

“The DNA polymerase apparently induces this unnatural base pair to form a structure that’s virtually indistinguishable from that of a natural base pair,” said Malyshev.

NaM and 5SICS, lacking hydrogen bonds, are held together in the DNA double-helix by “hydrophobic” forces, which cause certain molecular structures (like those found in oil) to be repelled by water molecules, and thus to cling together in a watery medium. “It’s very possible that these hydrophobic forces have characteristics that enable the flexibility and thus the replicability of the NaM-5SICS base pair,” said Romesberg. “Certainly if their aberrant structure in the double helix were held together by more rigid covalent bonds, they wouldn’t have been able to pop into the correct structure during DNA replication.”

An Arbitrary Choice?

The finding suggests that NaM-5SICS and potentially other, hydrophobically bound base pairs could some day be used to extend the DNA alphabet. It also hints that Evolution’s choice of the existing four-letter DNA alphabet—on this planet—may have been somewhat arbitrary. “It seems that life could have been based on many other genetic systems,” said Romesberg.

He and his laboratory colleagues are now trying to optimize the basic functionality of NaM and 5SICS, and to show that these new bases can work alongside natural bases in the DNA of a living cell.

“If we can get this new base pair to replicate with high efficiency and fidelity in vivo, we’ll have a semi-synthetic organism,” Romesberg said. “The things that one could do with that are pretty mind blowing.”

The other contributors to the paper, “KlenTaq polymerase replicates unnatural base pairs by inducing a Watson-Crick geometry,” are Thomas Lavergne of the Romesberg lab, Wolfram Welte and Kay Diederichs of the Marx lab, and Phillip Ordoukhanian of the Center for Protein and Nucleic Acid Research at The Scripps Research Institute.

Source: The Scripps Research Institute


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Larry H Bernstein, MD, FCAP, Reporter

A Pot[age] to Die For

A Pot[age] to Die For (Photo credit: jazzijava)

Neurodegerative Disease
Tumeric-Derived Compound Curcumin May Treat Alzheimer’s
Curry chemical shows promise for treating the memory-robbing disease
By Lauren K. Wolf
Department: Science & Technology
News Channels: Biological SCENE
Keywords: alternative medicine, dietary supplements, curcumin, tumeric, Alzheimer’s disease

Curcumin, derived from the rootstalk of the turmeric plant, not only gives Indian dishes their color but might treat Alzheimer’s.
Credit: Shutterstock
More than 5 million people in the U.S. currently live with Alzheimer’s disease. And according to the Alz­heimer’s Association, the situation is only going to get worse.
By 2050, the nonprofit estimates, up to 16 million Americans will have the memory-robbing disease. It will cost the U.S. $1.1 trillion annually to care for them unless a successful therapy is found.
Pharmaceutical companies have invested heavily in developing Alzheimer’s drugs, many of which target amyloid-β, a peptide that misfolds and clumps in the brains of patients. But so far, no amyloid-β-targeted medications have been successful. Expectation for the most advanced drugs—bapineu­zumab from Pfizer and Johnson & Johnson and solanezumab from Eli Lilly & Co.—are low on the basis of lackluster data from midstage clinical trials. That sentiment was reinforced last week when bapineuzumab was reported to have failed the first of four Phase III studies.
Even if these late-stage hopefuls do somehow work, they won’t come cheap, says Gregory M. Cole, a neuroscientist at the University of California, Los Angeles. These drugs “would cost patients tens of thousands of dollars per year,” he estimates. That hefty price tag stems from bapineuzumab and solanezumab being costly-to-manufacture monoclonal antibodies against amyloid-β.
“There’s a great need for inexpensive Alzheimer’s treatments,” as well as a backup plan if pharma fails, says Larry W. Baum, a professor in the School of Pharmacy at the Chinese University of Hong Kong. As a result, he says, a great many researchers have turned their attention to less pricy alternatives, such as compounds from plants and other natural sources.
Curcumin, a spice compound derived from the rootstalk of the turmeric plant (Curcuma longa), has stood out among some of the more promising naturally derived candidates.

When administered to mice that develop Alzheimer’s symptoms, curcumin decreases inflammation and reactive oxygen species in the rodents’ brains, researchers have found. The compound also inhibits the aggregation of troublesome amyloid-β strands among the animals’ nerve cells. But the development of curcumin as an Alzheimer’s drug has been stymied, scientists say, both by its low uptake in the body and a lack of funds for effective clinical trials—obstacles researchers are now trying to overcome.
In addition to contributing to curry dishes’ yellow color and pungent flavor, curcumin has been a medicine in India for thousands of years. Doctors practicing traditional Hindu medicine admire turmeric’s active ingredient for its anti-inflammatory properties and have used it to treat patients for ailments including digestive disorders and joint pain.
Only in the 1970s did Western researchers catch up with Eastern practices and confirm curcumin’s anti-inflammatory properties in the laboratory. Scientists also eventually determined that the polyphenolic compound is an antioxidant and has chemotherapeutic activity.

Bharat B. Aggarwal, a professor at the University of Texas M. D. Anderson Cancer Center, says curcumin is an example of a pleiotropic agent: It has a number of different effects and interacts with many targets and biochemical pathways in the body. He and his group have discovered that one important molecule targeted and subsequently suppressed by curcumin is NF-κB, a transcription factor that switches on the body’s inflammatory response when activated (J. Biol. Chem., DOI: 10.1074/jbc.270.42.24995).
Aside from NF-κB, curcumin seems to interact with several other molecules in the inflammatory pathway, a biological activity that Aggarwal thinks is advantageous. “All chronic diseases are caused by dysregulation of multiple targets,” he says. “Chemists don’t yet know how to design a drug that hits multiple targets.” With curcumin, “Mother Nature has already provided a compound that does so.”
Curcumin’s pleiotropy also brought it to the attention of UCLA’s Cole during the early 1990s while he was searching for possible Alzheimer’s therapeutics. “That was before we knew about amyloid-β” and its full role in Alzheimer’s, he says. “We were working on the disease from an oxidative damage and inflammation point of view—two processes implicated in aging.”
When Cole and his wife, Sally A. Frautschy, also at UCLA, searched the literature for compounds that could tackle both of these age-related processes, curcumin jumped out at them. It also didn’t hurt that the incidence of Alz­heimer’s in India, where large amounts of curcumin are consumed regularly, is lower than in other parts of the developing world (Lancet Neurol., DOI:10.1016/s1474-4422(08)70169-8).

In 2001, Cole, Frautschy, and colleagues published the first papers that demonstrated curcumin’s potential to treat neurodegenerative disease (Neurobiol. Aging, DOI: 10.1016/s0197-4580(01)00300-1; J. Neurosci.2001, 8370). The researchers studied the effects of curcumin on rats that had amyloid-β injected into their brains, as well as mice engineered to develop amyloid brain plaques. In both cases, curcumin suppressed oxidative tissue damage and reduced amyloid-β deposits.
Those results, Cole says, “turned us into curcuminologists.”
Although the UCLA team observed that curcumin decreased amyloid plaques in animal models, at the time, the researchers weren’t sure of the molecular mechanism involved.
Soon after the team’s first results were published, Cole recalls, a colleague brought to his attention the structural similarity between curcumin and the dyes used to stain amyloid plaques in diseased brain tissue. When Cole and Frautschy tested the spice compound, they saw that it, too, could stick to aggregated amyloid-β. “We thought, ‘Wow, not only is curcumin an antioxidant and an anti-inflammatory, but it also might be an anti-amyloid drug,’ ” he says.
In 2004, a group in Japan demonstrated that submicromolar concentrations of curcumin in solution could inhibit aggregation of amyloid-β and break up preformed fibrils of the stuff (J. Neurosci. Res., DOI: 10.1002/jnr.20025). Shortly after that, the UCLA team demonstrated the same (J. Biol. Chem., DOI: 10.1074/jbc.m404751200).
As an Alzheimer’s drug, however, it’s unclear how important it is that the spice compound inhibits amyloid-β aggregation, Cole says. “When you have something that’s so pleiotropic,” he adds, “it’s hard to know” which of its modes of action is most effective.
Having multiple targets may be what helps curcumin have such beneficial, neuroprotective effects, says David R. Schubert, a neurobiologist at the Salk Institute for Biological Studies, in La Jolla, Calif. But its pleiotropy can also be a detriment, he contends.
The pharmaceutical world, Schubert says, focuses on designing drugs aimed at hitting single-target molecules with high affinity. “But we don’t really know what ‘the’ target for curcumin is,” he says, “and we get knocked for it on grant requests.”
Another problem with curcumin is poor bioavailability. When ingested, UCLA’s Cole says, the compound gets converted into other molecular forms, such as curcumin glucuronide or curcumin sulfate. It also gets hydrolyzed at the alkaline and neutral pHs present in many areas of the body. Not much of the curcumin gets into the bloodstream, let alone past the blood-brain barrier, in its pure, active form, he adds.

Unfortunately, neither Cole nor Baum at the Chinese University of Hong Kong realized the poor bioavailability until they had each launched a clinical trial of curcumin. So the studies showed no significant difference between Alzheimer’s patients taking the spice compound and those taking a placebo (J. Clin. Psychopharma­col., DOI: 10.1097/jcp.0b013e318160862c).
“But we did show curcumin was safe for patients,” Baum says, finding a silver lining to the blunder. “We didn’t see any adverse effects even at high doses.”

Some researchers, such as Salk’s Schubert, are tackling curcumin’s low bioavailability by modifying the compound to improve its properties. Schubert and his group have come up with a molecule, called J147, that’s a hybrid of curcumin and cyclohexyl-bisphenol A. Like Cole and coworkers, they also came upon the compound not by initially screening for the ability to interact with amyloid-β, but by screening for the ability to alleviate age-related symptoms.

The researchers hit upon J147 by exposing cultured Alzheimer’s nerve cells to a library of compounds and then measuring changes to levels of biomarkers for oxidative stress, inflammation, and nerve growth. J147 performed well in all categories. And when given to mice engineered to accumulate amyloid-β clumps in their brains, the hybrid molecule prevented memory loss and reduced formation of amyloid plaques over time (PLoS One, DOI: 10.1371/journal.pone.0027865).

Other researchers have tackled curcumin’s poor bioavailability by reformulating it. Both Baum and Cole have encapsulated curcumin in nanospheres coated with either polymers or lipids to protect the compound from modification after ingestion. Cole tells C&EN that by packaging the curcumin in this way, he and his group have gotten micromolar quantities of it into the bloodstream of humans. The researchers are now preparing for a small clinical trial to test the formulation on patients with mild cognitive impairment, who are at an increased risk of developing Alzheimer’s.

An early-intervention human study such as this one comes with its own set of challenges, Cole says. People with mild cognitive impairment “have good days and bad days,” he says. A large trial over a long period would be the best way to get any meaningful data, he adds.  Such a trial can cost up to $100 million, a budget big pharma might be able to scrape together but that is far out of reach for academics funded by grants, Cole says. “If you’re down at the level of what an individual investigator can do, you’re running a small trial,” he says, “and even if the result is positive, it might be inconclusive” because of its small size or short duration. That’s one of the reasons the curcumin work is slow-going, Cole contends.
NIH-Funded Research Provides New Clues on How ApoE4 Affects Alzheimer’s Risk
Published: Tuesday, October 30, 2012
Last Updated: Tuesday, October 30, 2012

Researchers found that ApoE4 triggers an inflammatory reaction that weakens the blood-brain barrier.
Common variants of the ApoE gene are strongly associated with the risk of developing late-onset Alzheimer’s disease, but the gene’s role in the disease has been unclear.

Now, researchers funded by the National Institutes of Health have found that in mice, having the most risky variant of ApoE damages the blood vessels that feed the brain.

The researchers found that the high-risk variant, ApoE4, triggers an inflammatory reaction that weakens the blood-brain barrier, a network of cells and other components that lines brain’s brain vessels.

Normally, this barrier allows nutrients into the brain and keeps harmful substances out.

The study appears in Nature, and was led by Berislav Zlokovic, M.D., Ph.D., director of the Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles.

“Understanding the role of ApoE4 in Alzheimer’s disease may be one of the most important avenues to a new therapy,” Dr. Zlokovic said. “Our study shows that ApoE4 triggers a cascade of events that damages the brain’s vascular system,” he said, referring to the system of blood vessels that supply the brain.

The ApoE gene encodes a protein that helps regulate the levels and distribution of cholesterol and other lipids in the body. The gene exists in three varieties.

ApoE2 is thought to play a protective role against both Alzheimer’s and heart disease, ApoE3 is believed to be neutral, and ApoE4 confers a higher risk for both conditions.

Outside the brain, the ApoE4 protein appears to be less effective than other versions at clearing away cholesterol; however, inside the brain, exactly how ApoE4 contributes to Alzheimer’s disease has been a mystery.

Dr. Zlokovic and his team studied several lines of genetically engineered mice, including one that lacks the ApoE gene and three other lines that produce only human ApoE2, ApoE3 or ApoE4. Mice normally have only a single version of ApoE.

The researchers found that mice whose bodies made only ApoE4, or made no ApoE at all, had a leaky blood-brain barrier. With the barrier compromised, harmful proteins in the blood made their way into the mice’s brains, and after several weeks, the researchers were able to detect loss of small blood vessels, changes in brain function, and a loss of connections between brain cells.

“The study demonstrates that damage to the brain’s vascular system may play a key role in Alzheimer’s disease, and highlights growing recognition of potential links between stroke and Alzheimer’s-type dementia,” said Roderick Corriveau, Ph.D., a program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research. “It also suggests that we might be able to decrease the risk of Alzheimer’s disease among ApoE4 carriers by improving their vascular health.”

The researchers also found that ApoE2 and ApoE3 help control the levels of an inflammatory molecule called cyclophilin A (CypA), but ApoE4 does not. Levels of CypA were raised about five-fold in blood vessels of mice that produce only ApoE4.

The excess CypA then activated an enzyme, called MMP-9, which destroys protein components of the blood-brain barrier. Treatment with the immunosuppressant drug cyclosporine A, which inhibits CypA, preserved the integrity of the blood-brain barrier and lessened damage to the brain.

An inhibitor of the MMP-9 enzyme had similar beneficial effects. In prior studies, inhibitors of this enzyme have been shown to reduce brain damage after stroke in animal models.

“These findings point to cyclophilin A as a potential new drug target for Alzheimer’s disease,” said Suzana Petanceska, Ph.D., a program director at NIH’s National Institute on Aging (NIA), which also funded Dr. Zlokovic’s study.

“Many population studies have shown an association between vascular risk factors in mid-life, such as high blood pressure and diabetes, and the risk for Alzheimer’s in late-life. We need more research aimed at deepening our understanding of the mechanisms involved and to test whether treatments that reduce vascular risk factors may be helpful against Alzheimer’s.”

Alzheimer’s disease is the most common cause of dementia in older adults, and affects more than 5 million Americans. A hallmark of the disease is a toxic protein fragment called beta-amyloid that accumulates in clumps, or plaques, within the brain.

Gene variations that cause higher levels of beta-amyloid are associated with a rare type of Alzheimer’s that appears early in life, between age 30 and 60.

However, it is the ApoE4 gene variant that is most strongly tied to the more common, late-onset type of Alzheimer’s disease. Inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer’s disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.

Dr. Zlokovic’s study and others point to a complex interplay between beta-amyloid and ApoE4. On the one hand, beta-amyloid is known to build up in and damage blood vessels and cause bleeding into the brain.

On the other hand, Dr. Zlokovic’s data suggest that ApoE4 can damage the vascular system independently of beta-amyloid. He theorizes that this damage makes it harder to clear beta-amyloid from the brain.

Some therapies under investigation for Alzheimer’s focus on destroying amyloid plaques, but therapies designed to compensate for ApoE4 might help prevent the plaques from forming, he said.

Compound Could Become Alzheimer’s Treatment
Thu, 10/11/2012 – 1:29pm
A new molecule designed to treat Alzheimer’s disease has significant promise and is potentially the safest to date, according to researchers.

Purdue University professor Arun Ghosh designed the molecule, which is a highly potent beta-secretase inhibitor with unique features that ensure it goes only to its target and does not affect healthy physiological processes, he said.

“This molecule maintains the disease-fighting properties of earlier beta-secretase inhibitors, but is much less likely to cause harmful side effects,” said Ghosh, the Ian P. Rothwell Distinguished Professor of Chemistry and Medicinal Chemistry and Molecular Pharmacology. “The selectivity we achieved is unprecedented, which gives it great promise for the long-term medication required to treat Alzheimer’s. Each time a treatment misses its disease target and instead interacts with a healthy cell or molecule, damage is done that we call toxicity. Even low levels of this toxicity could build up over years and years of treatment, and an Alzheimer’s patient would need to be treated for the rest of his or her life.”

The new molecule shows a 7,000-fold selectivity for its target enzyme, which far surpasses the benchmark of a 1,000-fold selectivity for a viable treatment molecule, and dwarfs the selectivity values in the hundreds for past beta-secretase inhibitors, he said. A paper detailing the work will be published in an upcoming Alzheimer’s research issue of the Journal of Medicinal Chemistry and is currently available online. The National Institutes of Health funded the research.

Beta-secretase inhibitors, which could allow for intervention in the early stages of Alzheimer’s disease, have promise as a potential treatment. Several drugs based on this molecular target have made it to clinical trials, including one based on a molecule Ghosh designed previously. These molecules prevent the first step in a chain of events that leads to the formation of amyloid plaque in the brain, fibrous clumps of toxic proteins that are believed to cause the disease’s devastating symptoms.

The National Institute on Aging estimates that 5.1 million Americans suffer from Alzheimer’s disease, which leads to dementia by affecting parts of the brain that control thought, memory and language.

“Alzheimer’s is a progressive disease that destroys the brain and also destroys the quality of life for those who suffer from it,” Ghosh said. “It eventually robs people of their ability to recognize their own spouse or child and to complete basic tasks necessary for independence, like getting dressed. It is a truly devastating disease for those who suffer from it and for their friends and loved ones.”

Earlier versions of the beta-secretase inhibitor were able to stop and even reverse the progression of amyloid plaques in tests on mice, but potency and selectivity are only two of the three pillars of a viable Alzheimer’s treatment, Ghosh said. It has yet to be shown whether this molecule possesses the third pillar, the ability to be turned into an easily administered drug that passes through the blood-brain barrier.

Ghosh collaborates with Jordan Tang, the J.G. Puterbaugh Chair in Medical Research at the Oklahoma Medical Research Foundation, who in 2000 identified beta-secretase and its role in the progression of Alzheimer’s. Later that year Ghosh designed his first molecule that bound to and inhibited the activity of the enzyme. He has strived to create the needed improvements ever since.

Ghosh bypasses the usual lengthy process of trial and error in finding useful inhibitor molecules by using a structure-based design strategy. He uses the structures of the inhibitor bound to the enzyme as a guide to what molecular features are important for desirable and undesirable characteristics. Then he removes, replaces and adds molecular groups to amplify the desirable and eliminate the undesirable.

“I believe structure-based design is vital to the development of new and improved medicine,” said Ghosh, who also is a member of the Purdue University Center for Cancer Research. “These strategies have the potential to eliminate enormous costs and time needed in traditional random screening protocols for drug development. Structure-based strategies allow us to design molecules that do precisely what we need them to do with fewer undesirable side effects.”

Tang performed the X-ray crystallography and captured the crystal structures to reveal important insights and serve as a guide for Ghosh’s designs.

“Developing inhibitors into clinically useful drugs is an evolutionary process,” Tang said. “We learn what works and what doesn’t along the way, and the knowledge permits us to do better in the next step. The miracles of modern medicine are built on top of excellent scientific findings. We try to do good science and know that the consequence will be a better chance for conquering diseases and improving lives.”

Beta-secretase belongs to a class of enzymes called aspartyl proteases. Research into beta-secretase inhibitors faced setbacks when other aspartyl proteases similar in structure, called memapsin 1 and cathepsin D, were discovered and found to be involved in many important physiological processes. Earlier designed beta-secretase inhibitors were found also to work against the biologically necessary enzymes.

Ghosh’s team focused on developing ways to make the inhibitor more selective so that it would avoid these other, physiologically important enzymes. They compared the structures of beta-secretase and memapsin 1 as they interacted with the inhibitor to find an active area unique only to beta-secretase. Then they added a functional molecular feature that targets and interacts with the unique area, making the inhibitor more attractive to beta-secretase and less attractive to the other enzymes.

“The added feature serves as a bait on the inhibitor molecule that entices beta-secretase and also grabs onto it tightly, greatly enhancing its selectivity,” he said. “This is a fundamental insight into the origins of selectivity and ways to increase it.”
Ghosh said this work highlights an important purpose of academic research.

“Academic research lays out and shares the fundamentals to advance drug discovery,” he said. “Advances in treatment are built upon the basic research happening at universities.”

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