γ-Secretase inhibitors and modulators for Alzheimer’s disease
Article first published online: 28 NOV 2011
© 2011 The Author. Journal of Neurochemistry © 2011 International Society for Neurochemistry
Journal of Neurochemistry
Special Issue: Alzheimer’s Disease
Volume 120, Issue Supplement s1, pages 89–98, January 2012
How to Cite
Wolfe, M. S. (2012), γ-Secretase inhibitors and modulators for Alzheimer’s disease. Journal of Neurochemistry, 120: 89–98. doi: 10.1111/j.1471-4159.2011.07501.x
- Issue published online: 23 DEC 2011
- Article first published online: 28 NOV 2011
- Received July 18, 2011; revised manuscript received September 12, 2011; accepted September 20, 2011.
- active site;
- allosteric sites;
- chemical probes;
- docking site;
J. Neurochem. (2012) 120 (Suppl. 1), 89–98.
γ-Secretase is a membrane embedded aspartyl protease complex with presenilin as the catalytic component. Along with β-secretase, this enzyme produces the amyloid β-protein of Alzheimer’s disease (AD) from the amyloid β-protein precursor. Because of its key role in the pathogenesis of AD, γ-secretase has been a prime target for drug discovery, and many inhibitors of this protease have been developed. The therapeutic potential of these inhibitors is virtually negated by the fact that γ-secretase is an essential part of the Notch signaling pathway, rendering the compounds unacceptably toxic upon chronic exposure. However, these compounds have served as useful chemical tools for biological investigations. In contrast, γ-secretase modulators continue to be of keen interest as possible AD therapeutics. These modulators either shift amyloid β-protein production to shorter, less pathogenic peptides or inhibit the proteolysis of amyloid β-protein precursor selectively compared to that of Notch. The various chemical types of inhibitors and modulators will be discussed, along with their use as probes for basic biology and their potential as AD therapeutics.