[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.
Tomita
Taisuke
T
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo.
D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D013329:Structure-Activity Relationship
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases