Document Detail

Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation.
MedLine Citation:
PMID:  20852062     Owner:  NLM     Status:  MEDLINE    
AMP-activated protein kinase (AMPK) is a metabolic sensor involved in intracellular energy metabolism through the control of several homeostatic mechanisms, which include autophagy and protein degradation. Recently, we reported that AMPK activation by resveratrol promotes autophagy-dependent degradation of the amyloid-β (Aβ) peptides, the core components of the cerebral senile plaques in Alzheimer's disease. To identify more potent enhancers of Aβ degradation, we screened a library of synthetic small molecules selected for their structural similarities with resveratrol. Here, we report the identification of a series of structurally related molecules, the RSVA series, which inhibited Aβ accumulation in cell lines nearly 40 times more potently than did resveratrol. Two of these molecules, RSVA314 and RSVA405, were further characterized and were found to facilitate CaMKKβ-dependent activation of AMPK, to inhibit mTOR (mammalian target of rapamycin), and to promote autophagy to increase Aβ degradation by the lysosomal system (apparent EC(50) ∼ 1 μM). This work identifies the RSVA compounds as promising lead molecules for the development of a new class of AMPK activating drugs controlling mTOR signaling, autophagy, and Aβ clearance.
Valérie Vingtdeux; Pallavi Chandakkar; Haitian Zhao; Cristina d'Abramo; Peter Davies; Philippe Marambaud
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-09-17
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  25     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-05     Completed Date:  2011-03-08     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  219-31     Citation Subset:  IM    
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MeSH Terms
AMP-Activated Protein Kinases / genetics,  metabolism*
Amyloid beta-Peptides / genetics,  metabolism*
Anti-Inflammatory Agents, Non-Steroidal / chemistry,  pharmacology
Autophagy / drug effects*
Cell Line, Tumor
Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Enzyme Activation / drug effects
Enzyme Activators / chemical synthesis,  chemistry,  pharmacology*
HEK293 Cells
Lysosomes / drug effects,  metabolism
Mice, Inbred C57BL
Molecular Structure
Stilbenes / chemistry,  pharmacology
TOR Serine-Threonine Kinases / metabolism
Grant Support
P01 AT004511/AT/NCCAM NIH HHS; R37 AG022102/AG/NIA NIH HHS; R37 AG022102-09/AG/NIA NIH HHS; UL1-RR024996/RR/NCRR NIH HHS
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Anti-Inflammatory Agents, Non-Steroidal; 0/Enzyme Activators; 0/Stilbenes; EC Serine-Threonine Kinases; EC Protein Kinases; Q369O8926L/resveratrol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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