Alzheimer's Disease: Basic Aspects

Abstract

The deposition of amyloid β peptides (Aβ) in one of the pathological hallmarks of Alzheimer's disease (AD). Aβ are composed of 40-42 amino acid peptides that are proteolytically cleaved from β amyloid precursor proteins (βAPP). The deposition as diffuse plaques of a species of Aβ ending at the 42nd residue residue (Aβ42) is one of the earliest pathological changes of AD. Importantly, mutations in βAPP genes located in positions flanking the Aβ sequences have been shown to cosegregate with the clinical manifestations of AD in a subset of familial AD (FAD) pedigrees. Moreover, mutations in presenilin (PS) 1 and 2, novel polytopic membrane proteins that were identified as causative molecules for the majority of early onset FAD, also increase the secretion and deposition of Aβ42. These results support the notion that Aβ42 plays a key role in the pathogenesis of AD. Recently, it was suggested that PS1 is a coactivator of γ-cleavage of βAPP as well as γ-like cleavage of Notch protein which plays an essenitial role in morphogenesis and development. In addition, the pathogenic role of tau in neuronal death is highlighted based on the identification of mutations in tau gene in a dominantly-inherited neurode-generative dementia FTDP-17. These novel findings regarding the protein aggregates and causative genes for AD and related disorders will facilitate our understanding of the pathogenesis of AD, as well as development of therapeutic strategies against it.