Gamma-secretase: a catalyst of Alzheimer disease and signal transduction.

Gamma-secretase is a membrane-bound protease that cleaves within the transmembrane region of the amyloid precursor protein to generate the C termini of both major peptides that constitute the amyloid plaques found in Alzheimer disease (AD). Recent biochemical studies provide compelling evidence that presenilins, membrane-spanning proteins associated with early-onset familial AD, are novel aspartyl proteased that function within a macromolecular complex to mediate gamma-secretase activity. These new insights underscore the role of the presenilins in regulated intramembrane proteolysis and could possibly lead to the inhibition of gamma-secretase activity as a therapy for AD.