γ-Secretase inhibitors and Alzheimer’s disease

The existence of pathogenic mutations in β-APP and the presenilin genes provides strong support for the hypothesis that Aβ production and deposition contribute to the etiology of Alzheimer’s disease (AD). The heterogeneous carboxyl termini of Aβ molecules deposited in the hippocampus, cortex and cerebrovasculature of AD patients are generated by γ-secretase. The γ-secretase that generates the termini in vivo is a complex of proteins containing presenilin as an integral component. Drugs that modulate the production of Aβ by inhibiting γ-secretase could provide an effective therapy for AD, but like most disease targets, the γ-secretase appears to have more than a single function. The use of potent inhibitors has aided the discovery and characterization of γ-secretase functions and reinforced the concept that a successful drug must demonstrate selectivity for lowering Aβ without disrupting the function of γ-secretase targets. The discovery of drugs that can selectively inhibit β-APP cleavage is an important objective. This review focuses on studies that enhance our understanding of the effects of inhibiting γ-secretase and provide direction for developing effective and selective γ-secretase inhibitors as drugs to treat AD.