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Wednesday, June 30, 2010

Resveratrol and Amyloid Folding

Resveratrol and Amyloid Folding

As readers of this blog are probably aware, the prevailing theory of AD is that amyloid precursor protein is somehow aberrantly cleaved as it is secreted by neurons, and leads to the formation of beta-amyloid. Beta amyloid is a toxic “oligomer” or protein fragment that becomes improperly folded, and deposits into plaques. It is believed that the small oligomers of beta amyloid are more toxic than their larger aggregated counterparts (i.e.,amyloid fibrils), and in fact, the plaques may represent a way for the body to sequester such toxic oligomers.

In a recent paper, published in the Journal of Biological Chemistry, Dr. Peter Tessier and his co-authors generated beta-amyloid peptides packed together in five unique isoforms, or "arrangements" (monomer, soluble oligomer, non-toxic oligomer, fibrillar intermediates and amyloid fibrils). In their experiments, three of these arrangements were toxic to human cells, two were not.

Next, the researchers introduced Resveratrol. The Resveratrol reacted with the toxic arrangements of beta amyloid, neutralizing their toxicity by inducing remodeling of their arrangement into non-toxic forms. It did not affect the non-toxic arrangements. Finally, Resveratrol seems to remodel the toxic species in a dose-dependent manner, which speaks to an underlying selectivity.

The ADCS is planning to begin a study of Resveratrol in mild to moderate AD in 2011, which should shed light on this interesting finding.

Michael Rafii, MD, PhD
Associate Medical Director, ADCS

Ladiwala et al, Resveratrol selectively remodels soluble oligomers and fibrils of amyloid a{beta} into off-pathway conformers. Journal of Biological Chemistry, May 2010.
Author: Michael Rafii MD,PhD at 9:44 AM 0 Comments

Thursday, June 24, 2010

Age-Related Cataracts vs Amyloid Cataracts, a Distinction

Building on their previous discovery that people with Alzheimer's have beta-amyloid deposits that appear as unusual cataracts in the lens of the eye, a team of researchers led by Dr. Lee Goldstein at Boston University School of Medicine, has discovered that beta-amyloid also accumulates in the eyes of people with Down syndrome.

Down syndrome patients develop symptoms of Alzheimer's Disease often by the age of 30 because they have an extra copy of a key Alzheimer's gene (Amyloid Precursor Protein) that leads to increased beta-amyloid accumulation in the brain. This same protein that aggregates in the brain, also accumulates in the lens and leads to these unusual cataracts in Down syndrome. These cataracts are prevalent in people with Down syndrome and are sometimes seen at birth.

It is important to note that Alzheimer's Disease and Down Syndrome-associated cataracts are distinct from age-related cataracts, and typically localize in a different part of the lens. The discovery is leading the researchers to develop an innovative eye test for early detection of Alzheimer's pathology in both disorders.

Michael S. Rafii, MD, PhD
Associate Medical Director, ADCS

*Moncaster J et al. Alzheimer's Disease Amyloid-ß Links Lens and Brain Pathology in Down Syndrome. PLoS ONE, 2010
Author: Michael Rafii MD,PhD at 9:09 AM 0 Comments

Wednesday, June 16, 2010

Fibrinogen and AD


A relationship between vascular risk factors and Alzheimer disease has been considered for over 20 years. In fact, it was widely accepted that “a hardening of the arteries” was to blame for senile dementias. There is also evidence that vascular diseases such as stroke, atherosclerosis, and hypertension are associated with an increased risk of dementia and AD, and that an abnormally elevated level of fibrinogen, the protein critical for blood clot formation, is correlated with AD. Many epidemiologic studies show that practically all of the reported risk factors for AD are related to vascular functions and have an established association with cerebral hypoperfusion.

In the June 10 issue of the journal Neuron, a research team led by Sidney Strickland at Rockefeller University in New York City provides a link between the ß amyloid peptide (Aß) and abnormal fibrin clot formation in cerebral blood vessels. In essence, they suggest a new role for Aß in AD, whereby it would accumulate in the aging brain and interact with fibrinogen. This interaction is thought to lead to persistent clots that obstruct blood flow and engender inflammation. The researchers propose that this altered clotting, compromised blood flow, and inflammation, all contribute to the cognitive decline associated with AD.

This paper nicely establishes a link between fibrin clot formation and Aß protein in animal models of AD, and warrants further investigation, particularly in how this process might occur in the aging human brain.

In the meantime, it should be noted that aerobic exercise (in moderation), has been shown to exert the greatest influence on AD risk reduction, perhaps by optimally affecting cerebral perfusion.

Michael Rafii, MD, PhD
Associate Medical Director, ADCS

Cortes-Canteli M, Paul J, Norris EH, Bronstein R, Ahn HJ, Zamolodchikov D, Bhuvanendran S, Fenz KM, Strickland S. Fibrinogen and ß-Amyloid Association Alters Thrombosis and Fibrinolysis: A Possible Contributing Factor to Alzheimer’s Disease. Neuron. 2010 June 10;66:695-709.

Author: Michael Rafii MD,PhD at 4:33 PM 0 Comments

Tuesday, June 08, 2010

Testosterone and AD

Increasing evidence indicates that there are reductions in testosterone and estrogen levels in older men and women. These hormonal reductions may be risk factors for cognitive impairment and the development of Alzheimer's disease (AD). As testosterone levels decline as men age, there is an urge to treat this natural process with hormone replacement, just as it is done for many women undergoing menopause. The enzyme aromatase in the male brain converts some of the testosterone to the “female” hormone estrogen, which has its own neuroprotective features.

In a recent paper, researchers report that knocking out aromatase protects male transgenic mice against AD-like pathology and cognitive decline. In the knockout mice (which lacks the aromatase), testosterone is elevated in the brain, whih leads to a decrease in ß-secretase (BACE) and an increase in neprilysin—enzymes involved in the making and breaking, respectively, of amyloid-ß (Aß).

How does the increased testosterone prevent amyloid pathology? Testosterone can enhance Aß clearance via activating the enzyme neprilysin and decreasing BACE expression. As testosterone levels drop, more beta-amyloid is produced by BACE, and less beta-amyloid is removed by neprilysin. So, are we closer to a trial of testosterone for AD?

In fact, a small trial conducted at the University of California at Los Angeles found that male Alzheimer's patients given testosterone treatment reported some improvements to their caregivers in the parameters that measure quality of life. However, when these same patients were interviewed by clinicians involved in the study, no statistically significant improvement in cognitive function was measured.

Even so, the possibility of using testosterone for treatment of Alzheimer's remains an open question that is under investigation.

McAllister C, Long J, Bowers A, Walker A, Cao P, Honda S-I, Harada J, Staufenbiel M, Shen Y, Li R. Genetic targeting of aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. J. Neurosci 2010 May 26; 30:7326-7334.

Michael S. Rafii, MD, PhD
Associate Medical Director
Alzheimer's Disease Cooperative Study
Author: Michael Rafii MD,PhD at 3:53 PM 0 Comments

Wednesday, June 02, 2010

ApoE4 May Also Affect How AD Manifests Itself


The Alzheimer’s Disease Neuroimaging Initiative(ADNI) continues to provide us with greater, and more detailed information about AD. For quite some time, we have known that the ApoE4 genotype leads to an increased risk of developing sporadic AD. Patients with the ApoE4 gene (carriers) typically develop Alzheimer’s disease 5-7 years earlier than those without the gene (non-carriers). One or more copies of the ApoE4 gene are present in 20%-30% of the general population and in 45%-60% of patients with Alzheimer’s disease. But, some individuals with two copies of the ApoE4 gene however, never develop Alzheimer’s disease, and some non-carriers do. Hence, it is not currently used in routine clinical practice.

A recent study by Dr. Wolk from the University of Pennsylvania and Dr. Dickerson from Massachusetts General Hospital has shown that in addition to this influence on AD risk, ApoE4 may also affect how the disease manifests itself. They found that ApoE4 carriers had poor memory retention with greater medial temporal lobe atrophy, whereas non-carriers did worse on working memory tasks and had increased frontoparietal atrophy.

ApoE4 carriers and non-carriers showed striking differences in immediate and delayed recall in the Auditory Verbal Learning Test, which involved memorizing a list of 15 words. During the first learning trial, in which participants heard the list and repeated as many words as they could recall, the non-carriers actually did worse. Over time, though, some of the learned information gets transferred to long-term memory, and by the fifth trial, the E4 carriers and non-carriers were doing about the same, suggesting comparable overall learning. However, when asked to recall the words 30 minutes later, the E4 carriers did much worse than the non-carriers.

E4 carriers, who did comparatively worse on delayed recall, had smaller hippocampi and more cortical thinning in the medial temporal lobe, which is required for memory retention. Non-carriers, who had more trouble with immediate recall, had greater atrophy in parietal and frontal regions believed to mediate short-term memory storage. The cognitive deficits in each group correlated with atrophy in the brain regions that subserve those functions, which is a fundamental tenet of neurology.

What this means for the future of routine testing for ApoE4 remains to be seen, but such studies demonstrate that ApoE4 is likely to be mechanistically relevant to the development of AD, and its use as a diagnostic may play an important role in better characterizing patients.

Michael Rafii, MD, PhD
ADCS Associate Medical Director

Wolk DA, Dickerson BC, and the Alzheimer’s Disease Neuroimaging Initiative. Apolipoprotein E genotype has dissociable effects on memory and attentional-executive network function in Alzheimer’s disease. PNAS Early Edition. 17 May 2010
Author: Michael Rafii MD,PhD at 3:58 PM 0 Comments

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The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.