Regulation of APP cleavage by alpha-, beta- and gamma-secretases

Proteolytic cleavage of the amyloid protein from the amyloid protein precur sor (APP) by APP secretases is a key event in Alzheimer's disease (AD) path ogenesis, alpha-Secretases cleave APP within the amyloid sequences, whereas beta- and gamma-secretases cleave on the N- and C-terminal ends respective ly. The transmembrane aspartyl protease BACE has been identified as beta-se cretase and several proteases (ADAM-10, TACE, PC7) may be alpha-secretases. A number of studies have suggested that presenilins could be gamma-secreta ses, although this remains to be demonstrated conclusively, Inhibition of b eta- and gamma-secretase, or stimulation of alpha-secretase, is a rational strategy for therapeutic intervention in AD. (C) 2000 Federation of Europea n Biochemical Societies. Published by Elsevier Science B.V. All rights rese rved.