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FASEB J. 2011 Jan;25(1):219-31. doi: 10.1096/fj.10-167361. Epub 2010 Sep 17.

Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation.

Author information

  • 1Litwin-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.

Abstract

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.

PMID:
20852062
[PubMed - indexed for MEDLINE]
PMCID:
PMC3005419
Free PMC Article
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