Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation.
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.
Vingtdeux
Valérie
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Litwin-Zucker Research Center for the Study of Alzheimer's Disease, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Medical Center, Manhasset, New York, NY 11030, USA.
Chandakkar
Pallavi
P
Zhao
Haitian
H
d'Abramo
Cristina
C
Davies
Peter
P
Marambaud
Philippe
P
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014162:Transfection
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D020536:Enzyme Activators; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol