Inhibition and modulation of γ-secretase for Alzheimer's disease

The 4-kDa amyloid beta-peptide (A beta) is strongly implicated the pathogenesis of Alzheimer's disease (AD), and this peptide is cut out of the amyloid beta-protein precursor (APP) by the sequential action of beta- and gamma-secretases. gamma-Secretase is a membrane-embedded protease complex that cleaves the transmembrane region of APP to produce A beta, and this protease is a top target for developing AD therapeutics. A number of inhibitors of the gamma-secretase complex have been identified, including peptidomimetics that block the active site, helical peptides that interact with the initial substrate docking site, and other less peptide-like, more drug-like compounds. To date, one gamma-secretase inhibitor has advanced into late-phase clinical trials for the treatment of AD, but serious concerns remain. The gamma-secretase complex cleaves a number of other substrates, and gamma-secretase inhibitors cause in vivo toxicities by blocking proteolysis of one essential substrate, the Notch receptor. Thus, compounds that modulate gamma-secretase, rather than inhibit it, to selectively alter A beta production without hindering signal transduction from the Notch receptor would be more ideal. Such modulators have been discovered and advanced, with one compound in late-phase clinical trials, renewing interest in gamma-secretase as a therapeutic target.