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2005 | 52 | 2 | 417-423
Article title

Molecular mechanisms initiating amyloid β-fibril formation in Alzheimer's disease

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EN
Abstracts
EN
The deposition of aggregated amyloid β-protein (Aβ) in the human brain is a major lesion in Alzheimer' disease (AD). The process of Aβ fibril formation is associated with a cascade of neuropathogenic events that induces brain neurodegeneration leading to the cognitive and behavioral decline characteristic of AD. Although a detailed knowledge of Aβ assembly is crucial for the development of new therapeutic approaches, our understanding of the molecular mechanisms underlying the initiation of Aβ fibril formation remains very incomplete. The genetic defects responsible for familial AD influence fibrillogenesis. In a majority of familial cases determined by amyloid precursor protein (APP) and presenilin (PS) mutations, a significant overproduction of Aβ and an increase in the Aβ42/Aβ40 ratio are observed. Recently, it was shown that the two main alloforms of Aβ have distinct biological activity and behaviour at the earliest stage of assembly. In vitro studies demonstrated that Aβ42 monomers, but not Aβ40, form initial and minimal structures (pentamer/hexamer units called paranuclei) that can oligomerize to larger forms. It is now apparent that Aβ oligomers and protofibrils are more neurotoxic than mature Aβ fibrils or amyloid plaques. The neurotoxicity of the prefibrillar aggregates appears to result from their ability to impair fundamental cellular processes by interacting with the cellular membrane, causing oxidative stress and increasing free Ca^(2+)that eventually lead to apoptotic cell death.
Publisher

Year
Volume
52
Issue
2
Pages
417-423
Physical description
Dates
published
2005
received
2004-10-01
revised
2004-11-16
accepted
2004-12-08
(unknown)
2005-05-31
Contributors
  • Biochemistry Research, Aventis Pasteur Limited, Toronto, Ontario, Canada
author
  • Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
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Document Type
Publication order reference
Identifiers
YADDA identifier
bwmeta1.element.bwnjournal-article-abpv52i2p417kz
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