γ-Secretase as a target for Alzheimer's disease.

γ-Secretase is a protease complex responsible for cutting the transmembrane domain of the amyloid β-protein precursor (APP) to form the amyloid β-protein (Aβ), an aggregation-prone product that accumulates in the brain in Alzheimer's disease. As evidence suggests that Aβ is critical to Alzheimer pathogenesis, γ-secretase is considered a key target for the development of disease-modifying therapeutics. The protease complex cuts many other substrates, and some of these proteolytic events are part of signaling pathways or other important cellular functions. Among these, proteolysis of the Notch receptor is essential for signaling that is involved in a number of cell-fate determinations. Many inhibitors of γ-secretase have been identified, but it is clear that drug candidates for Alzheimer's disease should have minimal effects on the Notch signaling pathway, as serious safety issues have arisen with nonselective inhibitors. Two types of promising candidates that target this protease complex have emerged: the so-called "Notch-sparing" γ-secretase inhibitors, which block cleavage of APP selectively over that of Notch, and γ-secretase modulators, which shift the proportion of Aβ peptides produced in favor of shorter, less aggregation-prone species. The current status and prospects for these two general types of candidates will be discussed.