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

Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, New York 11030, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2010; 285(12):9100-13. DOI: 10.1074/jbc.M109.060061
Source: PubMed

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

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    • "The authors explained these negative results with the inefficacy of RESV in the central nervous system (CNS), since the treatment did not improve transcriptional response in the striatum, when compared with peripheral tissues [89]. However, previous studies showed that orally administered RESV could cross the blood–brain barrier and accumulate in the cerebral cortex, but not in the striatum or hippocampus [90]. Conversely, we observed that continuous intracutaneous administration of 1 mg/kg/day of RESV (a significant lower dose than the previous study [89]), for 28 days, significantly decreased histone H3 acetylation (H3K9) in both cortex and striatum of 9 month-old YAC128 mice, with significant improvement of motor coordination [Naia et al., unpublished data]. "
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    Biochimica et Biophysica Acta 07/2015; DOI:10.1016/j.bbadis.2015.07.003 · 4.66 Impact Factor
    • "Activated AMPK is abnormally accumulated in tangle-and pre-tangle-bearing neurons in AD patients and other tauopathies (Vingtdeux et al. 2011). AMPK activation has been shown to influence tau phosphorylation at Ser 262 , Ser 356 and Ser 396 (Yoshida and Goedert 2012; Thornton et al. 2011; Lee et al. 2013; Kim et al. 2015) and Ab production (Vingtdeux et al. 2010; Won et al. 2010; Chen et al. 2009), although the results were conflicting. This study was designed to investigate the effect of energy status on the production of Ab. "
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    Journal of Neural Transmission 06/2015; DOI:10.1007/s00702-015-1413-5 · 2.40 Impact Factor
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    • "One of the emerging therapeutic approaches involves modulation of cellular energetics that includes activation of AMP-activated protein kinase (AMPK), a master regulator of intracellular energy metabolism (Shirwany and Zou, 2014). AMPK activation was shown to promote neuronal survival after the exposure to Aβ peptides, induce autophagy-dependent degradation of Aβ, and reduce tau phosphorylation (Park et al., 2012; Salminen et al., 2011; Vingtdeux et al., 2010, 2011). Resveratrol-induced activation of AMPK reduced cognitive impairment in SAMP8 mouse model of AD (Porquet et al., 2013). "
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