[Pathogenesis of Alzheimer's disease: implications from amyloid research front].
Deposition of amyloid beta peptides as senile plaques is a hallmark lesion of Alzheimer's disease that is implicated in its pathogenesis. A beta is produced from amyloid precursor protein by sequential cleavages by beta- and gamma-secretases. Gamma-secretase is a membrane protease complex harboring presenilin as a catalytic subunit. Recent studies revealed how presenilin is assembled with its cofactor proteins and acquires the gamma-secretase activity: Aph-1 and nicastrin initially form a subcomplex to bind and stabilize presenilin, and then Pen-2 confers the gamma-secretase activity and facilitates endoproteolysis of presenilin. Understanding the mechanism of gamma-secretase cleavage will help to clarify how intercellular cell signaling through transmembrane proteins are regulated by intramembrane proteolysis, and eventually to cure Alzheimer's disease by inhibiting secretases.
Iwatsubo
Takeshi
T
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo.
D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human