At the frontline of Alzheimer's disease treatment: gamma-secretase inhibitor/modulator mechanism

Genetic and biological studies provide evidence that the production and deposition of amyloid-beta peptides (A beta) contribute to the etiology of Alzheimer's disease. beta- and gamma-secretases, which are responsible for the generation of A beta, are plausible molecular targets for Alzheimer's disease treatment. gamma-Secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain. This unusual enzyme is composed of a high molecular weight membrane protein complex containing presenilin, nicastrin, Aph-1 and Pen-2. Drugs that regulate the production of A beta by inhibiting or modulating gamma-secretase activity could provide a disease-modifying effect on Alzheimer's disease, although recent studies suggest that gamma-secretase plays important roles in cellular signaling including Notch. Thus, understanding the molecular mechanism whereby gamma-secretase recognizes and cleaves its substrate is a critical issue for the development of compounds that specifically regulate A beta-generating gamma-secretase activity. This review focuses on the structure and function relationship of gamma-secretase complex and the mode of action of the gamma-secretase inhibitors.