J. Neurochem. (2011) 116, 10–21.
Ectodomain shedding of the amyloid precursor protein (APP) by the metalloprotease activity α-secretase is a key regulatory event preventing the generation of the Alzheimer’s disease (AD) amyloid β peptide. Proteases similar to α-secretase are essential for diverse physiological processes, such as embryonic development, cell adhesion and neuronal guidance. Previously, several proteases were suggested as candidate α-secretases for APP, in particular members of the ADAM family (a disintegrin and metalloprotease). Two recent studies analyzed primary neurons, which are the cell type affected in AD, and finally demonstrated that the constitutively cleaving α-secretase activity is selectively mediated by ADAM10. An increase in α-secretase cleavage is considered a therapeutic approach for AD. However, the molecular mechanisms regulating α-secretase cleavage remain only partly understood. Signaling pathways activating protein kinase C and MAP kinase play a central role in stimulating α-secretase cleavage of APP. Additionally, several recent publications demonstrate that ADAM10 expression and α-secretase cleavage of APP are tightly controlled at the level of transcription, e.g. by retinoic acid receptors and sirtuins, and at the level of translation and protein trafficking. This review focuses on the recent progress made in unraveling the molecular identity, regulation and therapeutic potential of α-secretase in Alzheimer’s disease.