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Current Alzheimer Research
ISSN (Print): 1567-2050
ISSN (Online): 1875-5828
VOLUME: 5
ISSUE: 2
DOI: 10.2174/156720508783954767      Price:  $58









γ-Secretase Inhibition and Modulation for Alzheimers Disease

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Author(s): Michael S. Wolfe
Pages 158-164 (7)
Abstract:
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.
Affiliation:
Center for Neurologic Diseases,Harvard Medical School and Brigham and Women's Hospital, Boston,MA 02115, USA.