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 (Abeta) contribute to the etiology of Alzheimer's disease. beta- and gamma-secretases, which are responsible for the generation of Abeta, 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 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 Abeta-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.
Tomita
Taisuke
T
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. taisuke@mol.f.u-tokyo.ac.jp
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases