Substrate-based chemical probes for Alzheimer's γ-secretase

The membrane-embedded gamma-secretase complex carries out hydrolysis within the lipid bilayer in proteolyzing nearly 100 different membrane protein substrates. Among these substrates, the amyloid precursor protein (APP) has been the most studied, as generation of aggregation-prone amyloid beta-peptide (A beta) is a defining feature of Alzheimer's disease (AD). Mutations in APP and in presenilin, the catalytic component of gamma-secretase, cause familial AD, strong evidence for a pathogenic role of A beta. However, in human trials gamma-secretase inhibitors not only failed to slow AD progression, they worsened cognitive function. More in-depth study of gamma-secretase and how AD-causing mutations alter its structure and function is clearly needed. Substrate-based chemical probes have been critical to unraveling the complexity of gamma-secretase. Such synthetic peptides and peptidomimetics will be reviewed here, including recently reported structural and functional probes.