AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-β peptide metabolism

Valérie Vingtdeux, Luca Giliberto, Haitian Zhao, Pallavi Chandakkar, Qingli Wu, James E. Simon, Elsa M. Janle, Jessica Lobo, Mario G. Ferruzzi, Peter Davies, Philippe Marambaud

Research output: Contribution to journalArticlepeer-review

421 Scopus citations

Abstract

Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-β (Aβ) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Aβ levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls Aβ metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/calmodulin-dependent protein kinase kinase-β. Direct pharmacological and genetic activation of AMPK lowered extracellular Aβ accumulation, whereas AMPK inhibition reduced the effect of resveratrol on Aβ levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Aβ. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Aβ levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation ofAMPKhave therapeutic potential against Alzheimer disease.

Original languageEnglish (US)
Pages (from-to)9100-9113
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number12
DOIs
StatePublished - Mar 19 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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