[Molecular cell biology of presenilins].
Alzheimer's disease (AD), the most common cause of dementia in the elderly, is a progressive neurodegenerative disorder characterized pathologically by the presence of senile plaques and neurofibrillary tangles in the brains of affected individuals. Senile plaques are composed of amyloid-beta peptides (A beta), a proteolytic derivative of the beta-amyloid precursor protein (beta APP). A subset of AD is inherited as an autosomal dominant trait (familial AD, FAD). Mutations in genes encoding beta APP, presenilin (PS) 1 and PS2 are known to cause FAD. Genetic mutations in all three genes that cosegregate with FAD increase the production of the most amyloidogenic species, A beta 42. Moreover, PS1-deficient neurons exhibit severe defects in the production of A beta, suggesting that PS1 plays an important role in gamma-cleavage that liberates the C terminus of A beta. The physiological role of PS is still unknown, but data from studies in C. elegans, Drosophila and PS1 knock out mice suggests that PS1 plays a crucial role in Notch signaling, and recently it was shown that PS1 is required for the proteolytic release of the intracellular domain of Notch following activation of Notch by its ligand. Further studies on PS-mediated intra- and jaxtamembranous proteolysis will lead to the understanding of the pathological mechanism of AD as well as of a novel mode of membrane protein processing.
Tomita
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Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
Iwatsubo
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D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D053764:Presenilin-1; D053766:Presenilin-2
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2