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

Abstract

Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-␤ (A␤) 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␤ 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␤ 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-␤. Direct pharmacological and genetic activation of AMPK lowered extracellular A␤ accumulation, whereas AMPK inhibition reduced the effect of resveratrol on A␤ levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of A␤. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral A␤ levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease. Alzheimer disease (AD)2 is a progressive neurodegenerative disorder and the first cause of dementia. Amyloid-␤ (A␤) peptides have a central role in the pathogenesis of the disease and represent the core components of the senile plaques, the lesions invariably found in the neocortex and hippocampus of the AD brains (1, 2). In the amyloidogenic pathway, the amyloid-␤ precursor protein (APP) is sequentially cleaved by the aspartic protease ␤-secretase/BACE1 and by the ␥-secretase proteolytic complex to produce various A␤ peptides, including the most abundant isoforms A␤1-40 and A␤1-42 (3, 4).Epidemiological data suggest that moderate consumption of red wine is associated with a lower incidence of dementia and AD (5). The naturally occurring polyphenol resveratrol (trans-3,4Ј,5-trihydroxystilbene), which is found in abundance in red wine, has antioxidant and neuroprotective properties in vitro and could explain, in part, the beneficial effects of wine consumption in AD (6, 7). Importantly, resveratrol controls A␤ levels by facilitating its proteolytic clearance in cultured cell lines (8). However, the exact molecular mechanism by which resveratrol controls A␤ metabolism is currently unknown. Furthermore, evidence is missing to support the notion that orally administered resveratrol is bioavailable and bioactive in the brain.A growing body of literature has demonstrated the beneficial effect of resveratrol on age-related metabolic deterioration and its protective role in metabolic diseases, such as type 2 diabetes and obesity. Resveratrol mimics caloric restriction by extending the lifespan of different smal...

Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

“…As reported for young and middle-aged mice (Grossi et al, 2013), an astonishing activation of the autophagic lysosome system was observed also in 12-month-old Tg mice and, to a lesser extent, in age-matched wt controls. These data agree with a similar behavior displayed also by other natural phenols (Li et al, 2011;Vingtdeux et al, 2010) and, in our case, suggest that this pathway is involved in the removal of toxic Aß aggregates also in the advanced stage of the disease.…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…A current Phase II clinical trial that combines curcumin and yoga therapy aims to treat MCI (ClinicalTrials.gov identifier: NCT01811381). Resveratrol found in red grape skin is a potent antioxidant that has been shown to reduce amyloid plaque burden and improve memory deficits in transgenic AD mouse models [132,133]. Resveratrol activates the 5'adenosine monophosphate-activated protein kinase pathway, and stimulates activity of nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 [134,135], which subsequently activates the PGC1α metabolic regulatory pathway and promotes mitochondrial biogenesis [136][137][138][139].…”

“…Latrepirdine is proposed to interact with glutamate Reduces oxidative stress, reduces amyloid plaques, improves memory deficits in transgenic mouse models of AD No major effect on cognitive function [132][133][134][135][136][137][138][139] AD = Alzheimer's disease; ROS = reactive oxygen species; SOD = superoxide dismutase; MitoQ = mitoquinone mesylate; AMPK = adenosine monophosphate-activated protein kinase; NAD = nicotinamide adenine dinucleotide; SIRT1 = sirtuin 1 receptors, block voltage-dependent calcium channels, and inhibit mitochondrial permeability, thereby suppressing unnecessary mitophagy or apoptosis [153,154]. In a Phase II clinical trial in patients with moderate AD, it significantly improved cognitive function over placebo [155].…”

Proenergetic effects of resveratrol in the murine neuronal cell line Neuro2a

“…Experiments on AD transgenic mouse models with oral resveratrol administration showed that A levels and deposition were reduced in the cortex compared to controls [29]. Resveratrol pronouncedly decreased the amounts of secreted and intracellular A peptides generated from different cell lines by facilitating intracellular degradation of Aβ involving the proteasome [63].…”

“…Resveratrol has been found to activate AMPK in neuroblastoma cells and primary neurons in vitro as well as in the brain by activating calcium/CaMKKβ/AMPK signaling pathways [28,29].…”