AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid- Peptide Metabolism
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.
- SourceAvailable from: Luana Naia
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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 . 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 . Conversely, we observed that continuous intracutaneous administration of 1 mg/kg/day of RESV (a significant lower dose than the previous study ), 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both cortex and striatum of 9 month-old YAC128 mice, with significant improvement of motor coordination [Naia et al., unpublished data]. "
ABSTRACT: Sirtuins are a conserved family of NAD(+)-dependent class III lysine deacetylases, known to regulate longevity. In mammals, the sirtuin family has seven members (SIRT1-7), which vary in enzymatic activity, subcellular distribution and targets. Pharmacological and genetic modulation of SIRTs has been widely spread as a promising approach to slow aging and neurodegenerative processes. Huntington's disease (HD) is a neurodegenerative disorder linked to expression of polyglutamine-expanded huntingtin (HTT) protein for which there is still no disease-reversing treatment. Studies in different animal models provide convincing evidence that SIRT1 protects both cellular and animal models from mutant HTT toxicity, however controversial results were recently reported. Indeed, as a consequence of a variety of SIRT-activation pathways, either activation or inhibition of a specific SIRT appears to be neuroprotective. Therefore, this review summarizes the recent progress and knowledge in sirtuins (particularly SIRT1-3) and their implications for HD treatment. Copyright © 2015. Published by Elsevier B.V.Biochimica et Biophysica Acta 07/2015; DOI:10.1016/j.bbadis.2015.07.003 · 4.66 Impact Factor
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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. "
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.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). "
ABSTRACT: Development of therapeutic strategies to prevent Alzheimer's disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest that metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.03/2015; 82(4). DOI:10.1016/j.ebiom.2015.03.009