Alzheimer's disease treatment by inhibition/modulation of the γ-secretase activity

Abstract

Several lines of evidence indicate that the production and deposition of amyloid-β peptides (Aβ) contribute to the etiology of Alzheimer's disease. Inhibition or modulation of γ-secretase, that is a responsible enzyme for the Aβ production, is one of the plausible therapeutics for Alzheimer's disease. However, the γ-secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain of several membrane protein including APP and Notch receptor. Thus, development of drugs that regulate the production of Aβ without affecting the Notch signaling is now demanding. Extensive drug screening and development allow that some secretase inhibitors and modulators have advanced into late-phase clinical trials, whereas the molecular mechanisms of Notch-sparing effect by these compounds effect still remain unknown. Identification of the molecular targets and mechanisms of these compounds using chemical biological approaches is currently underway. This review focuses on the recent development of inhibitors/modulators and provides a direction for the effective treatment of AD through inhibition/modulation of the γ-secretase activity.