Document Detail


Piperidine acetic acid based γ-secretase modulators directly bind to Presenilin-1.
MedLine Citation:
PMID:  22229075     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Aβ42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. γ-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of Aβ42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the γ-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the γ-secretase complex leading to the observed modulation of γ-secretase activity.
Authors:
Christina J Crump; Benjamin A Fish; Suita V Castro; De-Ming Chau; Natalya Gertsik; Kwangwook Ahn; Cory Stiff; Nikolay Pozdnyakov; Kelly R Bales; Douglas S Johnson; Yue-Ming Li
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Publication Detail:
Type:  JOURNAL ARTICLE    
Journal Detail:
Title:  ACS chemical neuroscience     Volume:  2     ISSN:  1948-7193     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2012-1-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101525337     Medline TA:  ACS Chem Neurosci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  705-710     Citation Subset:  -    
Affiliation:
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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MeSH Terms
Descriptor/Qualifier:
Grant Support
ID/Acronym/Agency:
R01 NS076117-01//NINDS NIH HHS

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