γ-Secretase: characterization and implication for Alzheimer disease therapy

γ-Secretase is a membrane-bound protease that cleaves within the transmembrane region of amyloid precursor protein to generate the C-termini of the Aβ peptides which are believed to play a central role in the neuropathology of Alzheimer’s disease. An in vitro γ-secretase assay using a recombinant substrate C100Flag has been developed to facilitate the characterization and identification of this enigmatic protease. Biochemical studies establish that γ-secretase activity is catalyzed by a PS1-containing macromolecular complex. Moreover, the fact that the photoreactive active γ-secretase inhibitor directed to the active site labels PS1 suggests that PS1 contains the active site of the protease. Presenilin/γ-secretase as a potential target for AD therapy and its role in regulated intramembrane proteolysis are discussed.