July 4, 2011
Overlooked Peptide Reveals Clues To Causes Of Alzheimer’s Disease
Highly aggregative and neurotoxic amyloid peptide A-beta-43 points the way to new approaches for AD diagnosis and treatment
Researchers at the RIKEN Brain Science Institute (BSI) and their collaborators have shed light on the function of a little-studied amyloid peptide in promoting Alzheimer's disease (AD). Their surprising findings reveal that the peptide is more abundant, more neurotoxic, and exhibits a higher propensity to aggregate than amyloidogenic agents studied in earlier research, suggesting a potential role in new approaches for preventing AD-causing amyloidosis.
One hypothesis that has attracted widespread support proposes that AD is caused by the buildup of the senile plaques, and in particular of their main constituent, amyloid-Ã² peptides (AÃ²). Two major forms of AÃ², AÃ²40 and AÃ²42, have been associated with genetic mutations causing early-onset AD, and have thus received considerable research attention. The role of longer AÃ² species, in contrast, which also exist in the brains of Alzheimer's patients, has not yet been fully investigated.
In their current work, the researchers focused on AÃ²43, an amyloid-Ã² peptide found just as often in patient brains as AÃ²42, but about which relatively little is known. To study the peptide's role in AD, they generated mice with a mutation causing overproduction of AÃ²43, and used a highly sensitive system to distinguish between concentrations of AÃ²40, AÃ²42 and AÃ²43.
Their surprising results reveal that AÃ²43 is even more abundant in the brains of AD patients than AÃ²40, and more neurotoxic than AÃ²42. AÃ²43 also exhibits the highest propensity to aggregate and considerably accelerates amyloid pathology. Moreover, unlike the other two AÃ² species, which exist in human and mouse brains at birth, AÃ²43 levels appear to increase with age, consistent with the pattern of AD onset.
Published in the journal Nature Neuroscience, the findings thus reveal the possible value of AÃ²43 as a biomarker for diagnosis of AD and suggest a potential role in new approaches for preventing AD-causing amyloidosis, promising hope to AD sufferers around the world.
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