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


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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    ABSTRACT: It is currently thought that the lackluster performance of translational paradigms in the prevention of age-related cognitive deteriorative disorders, such as Alzheimer's disease (AD), may be due to the inadequacy of the prevailing approach of targeting only a single mechanism. Age-related cognitive deterioration and certain neurodegenerative disorders, including AD, are characterized by complex relationships between interrelated biological phenotypes. Thus, alternative strategies that simultaneously target multiple underlying mechanisms may represent a more effective approach to prevention, which is a strategic priority of the National Alzheimer's Project Act and the National Institute on Aging. In this review article, we discuss recent strategies designed to clarify the mechanisms by which certain brain-bioavailable, bioactive polyphenols, in particular, flavan-3-ols also known as flavanols, which are highly represented in cocoa extracts, may beneficially influence cognitive deterioration, such as in AD, while promoting healthy brain aging. However, we note that key issues to improve consistency and reproducibility in the development of cocoa extracts as a potential future therapeutic agent requires a better understanding of the cocoa extract sources, their processing, and more standardized testing including brain bioavailability of bioactive metabolites and brain target engagement studies. The ultimate goal of this review is to provide recommendations for future developments of cocoa extracts as a therapeutic agent in AD.
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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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    • "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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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia in the elderly. Accumulation of Aβ peptides in the brain has been suggested as the cause of AD (amyloid cascade hypothesis); however, the mechanism for the abnormal accumulation of Aβ in the brains of AD patients remains unclear. A plethora of evidence has emerged to support a link between metabolic disorders and AD. This study was designed to examine the relationship between energy status and Aβ production. Neuro 2a neuroblastoma cells overexpressing human amyloid precursor protein 695 (APP cells) were cultured in media containing different concentrations of glucose and agonist or antagonist of AMP-activated-protein-kinase (AMPK), a metabolic master sensor. The results showed that concentrations of glucose in the culture media were negatively associated with the activation statuses of AMPK in APP cells, but positively correlated with the levels of secreted Aβ. Modulating AMPK activities affected the production of Aβ. If APP cells were cultured in high glucose medium (i.e., AMPK was inactive), stimulation of AMPK activity decreased the production levels of Aβ. On the contrary, if APP cells were incubated in medium containing no glucose (i.e., AMPK was activated), inhibition of AMPK activity largely increased Aβ production. As AMPK activation is a common defect in metabolic abnormalities, our study supports the premise that metabolic disorders may aggravate AD pathogenesis.
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