Current Alzheimer Research

Prof. Debomoy K. Lahiri  
Department of Psychiatry, Indiana University School of Medicine
Neuroscience Research Center
Indianapolis, IN 46202


γ-Secretase Inhibition and Modulation for Alzheimers Disease

Author(s): Michael S. Wolfe

Affiliation: Center for Neurologic Diseases,Harvard Medical School and Brigham and Women's Hospital, Boston,MA 02115, USA.


γ-Secretase is a multi-protein complex that proteolyzes the transmembrane region of the amyloid β-peptide (Aβ) precursor (APP), producing the Aβ peptide implicated in the pathogenesis of Alzheimers disease (AD). This protease has been a top target for AD, and various inhibitors have been identified, including transition-state analogue inhibitors that interact with the active site, helical peptides that interact with the initial substrate docking site, and other less peptidelike, more drug-like compounds. Although one γ-secretase inhibitor has advanced into late-phase clinical trials, concerns about inhibiting this protease remain. The protease complex cleaves a number of other substrates, and in vivo toxicities observed with γ-secretase inhibitors are apparently due to blocking one particularly important substrate, the Notch receptor. Thus, the potential of γ-secretase as therapeutic target likely depends on the ability to selectively inhibit Aβ production without hindering Notch proteolysis (i.e., modulation rather than inhibition). The discovery of γ-secretase modulators has revived γ-secretase as an attractive target and has so far resulted in one compound in late-phase clinical trials. The identification of other modulators in a variety of structural classes raise the hope that more promising agents will soon be in the pipeline.

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Article Details

Page: [158 - 164]
Pages: 7
DOI: 10.2174/156720508783954767