[Targeting the structure and function relationships of the gamma-secretase for the development of Alzheimer's disease].

Genetic and biological studies provide evidence that the production and deposition of amyloid-beta peptides (Abeta) contribute to the etiology of Alzheimer's disease. Thus, beta- and gamma-secretases, that are involved in the Abeta generation, 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 Abeta by inhibiting or modulating gamma-secretase activity could provide a disease-modifying effect on AD, although recent studies suggest that gamma-secretase plays important roles in cellular signaling including Notch pathway. 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 Abeta-generating gamma-secretase activity. I will review our structural studies on the gamma-secretase complex, and envision the direction for developing effective and selective gamma-secretase inhibitors as therapeutics for AD.