Amyloid-β aggregation

Alzheimer's disease (AD) is the most prevalent neuroclegenerative disease in the growing population of elderly people. A hallmark of AD is the accumulation of plaques in the brain of AD patients. The plaques predominantly consist of aggregates of amyloid-beta (A beta), a pepticle of 39-42 amino acids generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein. There is a growing body of evidence that A,6 aggregates are ordered oligomers and the cause rather than a product of AD. The analysis of the assembly pathway of A beta in vitro and biochemical characterization of A)3 deposits isolated from AD brains indicate that A,8 oligomerization occurs via distinct intermediates, including oligomers of 3-50 A beta monomers, annular oligomers, protofibrils, fibrils and plaques. Of these, the most toxic species appear to be small A,8 oligomers. This article reviews the current knowledge of the mechanism of A,8 assembly in vivo and in vitro, as well as the influence of inherited amino acid replacements in A,6 and experimental conditions on A,8 aggregation. Challenges regarding the reproducible handling of the AP pepticle for in vitro assembly studies are discussed. Copyright (C) 2007 S. Karger AG, Basel.