NDLI: Inhibition and modulation of γ-secretase for Alzheimer’s disease

Content Provider	Springer Nature Link
Author	Wolfe, Michael S.
Copyright Year	2008
Abstract	The 4-kDa amyloid β-peptide (Aβ) is strongly implicated the pathogenesis of Alzheimer’s disease (AD), and this peptide is cut out of the amyloid β-protein precursor (APP) by the sequential action of β- and γ-secretases. γ-Secretase is a membrane-embedded protease complex that cleaves the transmembrane region of APP to produce Aβ, and this protease is a top target for developing AD therapeutics. A number of inhibitors of the γ-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 γ-secretase inhibitor has advanced into late-phase clinical trials for the treatment of AD, but serious concerns remain. The γ-secretase complex cleaves a number of other substrates, and γ-secretase inhibitors cause in vivo toxicities by blocking proteolysis of one essential substrate, the Notch receptor. Thus, compounds that modulate γ-secretase, rather than inhibit it, to selectively alter Aβ 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 γ-secretase as a therapeutic target.
Starting Page	391
Ending Page	398
Page Count	8
File Format	PDF
ISSN	19337213
Journal	NeuroRX
Volume Number	5
Issue Number	3
e-ISSN	18787479
Language	English
Publisher	Springer-Verlag
Publisher Date	2008-01-01
Publisher Institution	American Society for Experimental NeuroTherapeutics
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Alzheimer’s disease amyloid β-protein amyloid precursor protein Notch receptor secretase γ-secretase Neurosciences Neurology Neurosurgery Neurobiology
Content Type	Text
Resource Type	Article
Subject	Neurology (clinical) Pharmacology Pharmacology (medical)

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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