The membrane-embedded γ-
secretase complex carries out hydrolysis within the
lipid bilayer in proteolyzing nearly 150 different
membrane protein substrates. Among these substrates, the
amyloid precursor
protein (APP) has been the most studied, as generation of aggregation-prone
amyloid β-
protein (Aβ) is a defining feature of
Alzheimer's disease (AD). Mutations in APP and in
presenilin, the catalytic component of γ-
secretase, cause familial AD, strong evidence for a pathogenic role of Aβ. Substrate-based chemical probes-synthetic
peptides and
peptidomimetics-have been critical to unraveling the complexity of γ-
secretase, and small drug-like inhibitors and modulators of γ-
secretase activity have been essential for exploring the potential of the
protease as a therapeutic target for
Alzheimer's disease. Such chemical probes and therapeutic prototypes will be reviewed here, with concluding commentary on the future directions in the study of this biologically important
protease complex and the translation of basic findings into
therapeutics.