[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.