Role of water-soluble amyloid-β in the pathogenesis of Alzheimer's disease

Abstract

Water-soluble amyloid-β (wsAβ) is present in cerebral cortex of subjects at risk of Alzheimer's disease (AD) as well as in normal elderly subjects as a mixture of three major amyloid-β (Aβ) species: 1-42, py3-42 and py11-42. The three wsAβ species are nondetectable in brains of young people, free of immunohistochemically detectable amyloid plaques. In the brains of Down's syndrome and APP-mutant transgenic mice, wsAβ appears long time before amyloid deposition, indicating that it represent the first form of Aβ aggregation and accumulation. In normal brain, wsAβ is bound to apolipoprotein E that favours its degradation by proteases. The composition of wsAβ, in terms of the ratio between the full-length 1-42 and the py3-42 peptides, correlates with the severity of clinical and pathological phenotype in familial early onset AD. Water-soluble Aβ is the native counterpart of the Aβ small aggregates (soluble oligomers) that show in vitro an early and high neuronal toxicity. © 2005 Blackwell Publishing Ltd.