AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-β Peptide Metabolism

• Published in: The Journal of biological chemistry Vol. 285; no. 12; pp. 9100 - 9113
• Main Authors: Vingtdeux, Valérie, Giliberto, Luca, Zhao, Haitian, Chandakkar, Pallavi, Wu, Qingli, Simon, James E., Janle, Elsa M., Lobo, Jessica, Ferruzzi, Mario G., Davies, Peter, Marambaud, Philippe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.03.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Alzheimer Disease - metabolism; AMP-Activated Protein Kinases - metabolism; Amyloid beta-Peptides - chemistry; Animals; Autophagy; Calcium - metabolism; Cytosol - metabolism; Diseases/Alzheimer Disease; Diseases/Amyloid; Enzyme Inhibitors - pharmacology; Humans; Lysosomes - metabolism; Male; Mice; Mice, Transgenic; Neurobiology; Neurons - metabolism; Proteases/Secretases; Resveratrol; Signal Transduction; Signal Transduction/Calcium; Signal Transduction/Protein Kinases; Stilbenes - pharmacology; Diseases/Alzheimer Disease; Resveratrol; Signal Transduction/Calcium; Proteases/Secretases; Autophagy; Signal Transduction/Protein Kinases; Diseases/Amyloid
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.060061

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 of AMPK have therapeutic potential against Alzheimer disease.