Journal
NEUROTHERAPEUTICS
Volume 5, Issue 3, Pages 391-398Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.nurt.2008.05.010
Keywords
Alzheimer's disease; amyloid beta-protein; amyloid precursor protein; Notch receptor; secretase; gamma-secretase
Funding
- NIA NIH HHS [R01 AG017574-08, R01 AG017574] Funding Source: Medline
- NINDS NIH HHS [R01 NS041355-07, R01 NS041355] Funding Source: Medline
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The 4-kDa amyloid beta-peptide (A beta) is strongly implicated the pathogenesis of Alzheimer's disease (AD), and this peptide is cut out of the amyloid beta-protein precursor (APP) by the sequential action of beta- and gamma-secretases. gamma-Secretase is a membrane-embedded protease complex that cleaves the transmembrane region of APP to produce A beta, and this protease is a top target for developing AD therapeutics. A number of inhibitors of the gamma-secretase complex have been identified, including peptidomimetics that block the active site, helical peptides that interact with the initial substrate docking site, and other less peptide-like, more drug-like compounds. To date, one gamma-secretase inhibitor has advanced into late-phase clinical trials for the treatment of AD, but serious concerns remain. The gamma-secretase complex cleaves a number of other substrates, and gamma-secretase inhibitors cause in vivo toxicities by blocking proteolysis of one essential substrate, the Notch receptor. Thus, compounds that modulate gamma-secretase, rather than inhibit it, to selectively alter A beta production without hindering signal transduction from the Notch receptor would be more ideal. Such modulators have been discovered and advanced, with one compound in late-phase clinical trials, renewing interest in gamma-secretase as a therapeutic target.
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