Development of γ-secretase modulators;an update

Taisuke Tomita

Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo

Genetic and biological studies provide strong evidence that the production and deposition of amyloid-β peptides (Aβ) contribute to the etiology of Alzheimer's disease (AD).γ-Secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain and responsible to generation of C terminus of Aβ. Recently, much attention has been focused on drugs called γ-secretase modulators (GSMs) that specifically regulate the production of Aβ42 by modulating the γ-secretase activity. Understanding the molecular mechanism whereby the γ-secretase cleaves its substrate and GSM regulates the activity is a critical issue for the development of compounds for the treatment of AD without severe adverse effects.

Address correspondence to Dr.Taisuke Tomita, Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo(7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan)