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

Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-beta (A beta) 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 A beta 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 A beta 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-beta. Direct pharmacological and genetic activation of AMPK lowered extracellular A beta accumulation, whereas AMPK inhibition reduced the effect of resveratrol on A beta levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of A beta. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral A beta levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation ofAMPKhave therapeutic potential against Alzheimer disease.