AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta 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: Susana Esteban[Show abstract] [Hide abstract]
ABSTRACT: Ageing is an inevitable and multifactorial biological process. Free radicals have been implicated in ageing processes; it is hypothesized that they cause cumulative oxidative damage to crucial macromolecules and are responsible for failure of multiple physiological mechanisms. However, recent investigations have also suggested that free radicals can act as modulators of several signaling pathways such as those related to sirtuins. Caloric restriction is a non-genetic manipulation that extends lifespan of several species and improves healthspan; the belief that many of these benefits are due to the induction of sirtuins has led to the search for sirtuin activators, especially sirtuin 1, the most studied. Resveratrol, a polyphenol found in red grapes, was first known for its antioxidant and antifungal properties, and subsequently has been reported several biological effects, including the activation of sirtuins. Endogenously-produced melatonin, a powerful free radical scavenger, declines with age and its loss contributes to degenerative conditions of ageing. Recently, it was reported that melatonin also activates sirtuins, in addition to other functions, such as regulator of circadian rhythms or anti-inflammatory properties. The fact that melatonin and resveratrol are present in various foods, exhibiting possible synergistic effects, suggests the use of dietary ingredients to promote health and longevity. Copyright © 2015. Published by Elsevier Ireland Ltd.Mechanisms of ageing and development 03/2015; 146. DOI:10.1016/j.mad.2015.03.008 · 3.51 Impact Factor
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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.
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ABSTRACT: Compared to the rare familial early onset Alzheimer's disease (AD) that results from gene mutations in AbPP and presenilin-1, the pathogenesis of sporadic AD is much more complex and is believed to result from complex interactions between nutritional, environmental, epigenetic and genetic factors. Among those factors, the presence APOE4 is still the single strongest genetic risk factor for sporadic AD. However, the exact underlying mechanism whereby apoE4 contributes to the pathogenesis of sporadic AD remains unclear. Here, we discuss how altered cholesterol intracellular trafficking as a result of apoE4 might contribute to the development of pathological hallmarks of AD including brain deposition of amyloid beta (Ab), neurofibrillary tangles, and synaptic dysfunction.