[Alzheimer's disease: basic aspects].
The deposition of amyloid beta peptides (A beta) in one of the pathological hallmarks of Alzheimer's disease (AD). A beta are composed of 40-42 amino acid peptides that are proteolytically cleaved from beta amyloid precursor proteins (beta APP). The deposition as diffuse plaques of a species of A beta ending at the 42nd residue residue (A beta 42) is one of the earliest pathological changes of AD. Importantly, mutations in beta APP genes located in positions flanking the A beta 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 polytropic membrane proteins that were identified as causative molecules for the majority of early onset FAD, also increase the secretion and deposition of A beta 42. These results support the notion that A beta 42 plays a key role in the pathogenesis of AD. Recently, it was suggested that PS1 is a coactivator of gamma-cleavage of beta APP as well as gamma-like cleavage of Notch protein which plays an essential 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 neurodegenerative 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.
Iwatsubo
T
T
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo.
D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D003704:Dementia / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009154:Mutation; D053764:Presenilin-1; D053766:Presenilin-2; D016875:tau Proteins / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C054369:MAPT protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D016875:tau Proteins