Presenilins and γ-Secretase: Structure, Function, and Role in Alzheimer Disease

Presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD). The encoded multipass membrane proteins were subsequently found to be the catalytic components of gamma-secretases, membrane-embedded aspartyl protease complexes responsible for generating the carboxyl terminus of theamyloid beta-protein (A beta) from the amyloid protein precursor (APP). The protease complex also cleaves a variety of other type I integralmembrane proteins, most notably the Notch receptor, signaling from which is involved in many cell differentiation events. Although gamma-secretase is a top target for developing disease-modifying AD therapeutics, interference with Notch signaling should be avoided. Compounds that alter A beta production by gamma-secretase without affecting Notch proteolysis and signaling have been identified and are currently at various stages in the drug development pipeline.