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Novel synthetic small‐molecule activators of AMPK as enhancers of autophagy and amyloid‐β peptide degradation
Author(s) -
Vingtdeux Valérie,
Chandakkar Pallavi,
Zhao Haitian,
d'Abramo Cristina,
Davies Peter,
Marambsud Philippe
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-167361
Subject(s) - ampk , autophagy , resveratrol , chemistry , microbiology and biotechnology , pi3k/akt/mtor pathway , protein kinase a , small molecule , biochemistry , kinase , signal transduction , biology , apoptosis
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, autoph‐agy, and Aβ clearance.—Vingtdeux, V., Chandakkar, P., Zhao, H., d'Abramo, C., Davies, P., Marambaud, P. Novel synthetic small‐molecule activators of AMPK as enhancers of autophagy and amyloid‐β peptide degradation. FASEB J. 25, 219–231 (2011). www.fasebj.org