Regulation of APP cleavage by α‐, β‐ and γ‐secretases

Proteolytic cleavage of the amyloid protein from the amyloid protein precursor (APP) by APP secretases is a key event in Alzheimer's disease (AD) pathogenesis. α‐Secretases cleave APP within the amyloid sequences, whereas β‐ and γ‐secretases cleave on the N‐ and C‐terminal ends respectively. The transmembrane aspartyl protease BACE has been identified as β‐secretase and several proteases (ADAM‐10, TACE, PC7) may be α‐secretases. A number of studies have suggested that presenilins could be γ‐secretases, although this remains to be demonstrated conclusively. Inhibition of β‐ and γ‐secretase, or stimulation of α‐secretase, is a rational strategy for therapeutic intervention in AD.