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...

AMP-activated protein kinase (AMPK) is a metabolic sensor involved in intracellular energy metabolism through the control of several homeostatic mechanisms, which include autophagy and protein degradation. Recently, we reported that AMPK activation by resveratrol promotes autophagy-dependent degradation of the amyloid-β (Aβ) peptides, the core components of the cerebral senile plaques in Alzheimer's disease. To identify more potent enhancers of Aβ degradation, we screened a library of synthetic small molecules selected for their structural similarities with resveratrol. Here, we report the identification of a series of structurally related molecules, the RSVA series, which inhibited Aβ accumulation in cell lines nearly 40 times more potently than did resveratrol. Two of these molecules, RSVA314 and RSVA405, were further characterized and were found to facilitate CaMKKβ-dependent activation of AMPK, to inhibit mTOR (mammalian target of rapamycin), and to promote autophagy to increase Aβ degradation by the lysosomal system (apparent EC(50) ∼ 1 μM). This work identifies the RSVA compounds as promising lead molecules for the development of a new class of AMPK activating drugs controlling mTOR signaling, autophagy, and Aβ clearance.

Calcium homeostasis modulator 1 (CALHM1) is a Ca2+ channel controlling neuronal excitability and potentially involved in the pathogenesis of Alzheimer's disease (AD). Although strong evidence indicates that CALHM1 is required for neuronal electrical activity, its role in intracellular Ca2+ signaling remains unknown. Here, we show that in hippocampal HT-22 cells, CALHM1 expression led to a robust and relatively selective activation of the Ca2+-sensing kinases, ERK1/2. CALHM1 also triggered activation of MEK1/2, the upstream ERK1/2-activating kinases, and of RSK1/2/3 and MSK1, two downstream effectors of ERK1/2 signaling. CALHM1-mediated activation of ERK1/2 signaling was controlled by the small GTPase Ras. Pharmacological inhibition of CALHM1 permeability using ruthenium red, Zn2+, and Gd3+, or expression of the CALHM1 N140A and W114A mutants, which are deficient in mediating Ca2+ influx, prevented the effect of CALHM1 on the MEK/ERK/RSK/MSK signaling cascade, demonstrating that CALHM1 controlled this pathway via its Ca2+ channel properties. Importantly, expression of CALHM1 bearing the natural P86L polymorphism, which leads to a partial loss of CALHM1 function and is associated with an earlier age at onset in AD patients, showed reduced activation of ERK1/2, RSK1/2/3, and MSK1. In line with these results obtained in transfected cells, primary cerebral neurons isolated from Calhm1 knockout mice showed significant impairments in the activation of MEK/ERK/RSK/MSK signaling. This work identifies a previously uncharacterized mechanism of control of Ca2+-dependent ERK1/2 signaling in neurons, and further establishes CALHM1 as a critical ion channel for neuronal signaling and function.

Neurofibrillary tangles (NFTs) are the pathological hallmark of neurodegenerative diseases commonly known as tauopathies. NFTs result from the intracellular aggregation of abnormally and hyperphosphorylated tau proteins. Tau functions, which include the regulation of microtubules dynamics, are dependent on its phosphorylation status. As a consequence, any changes in tau phosphorylation can have major impacts on synaptic plasticity and memory. Recently, it has been demonstrated that AMP-activated protein kinase (AMPK) was deregulated in the brain of Alzheimer’s disease (AD) patients where it co-localized with phosphorylated tau in pre-tangle and tangle-bearing neurons. Besides, it was found that AMPK was a tau kinase in vitro. Here, we find that endogenous AMPK activation in mouse primary neurons induced an increase of tau phosphorylation at multiple sites, whereas AMPK inhibition led to a rapid decrease of tau phosphorylation. We further show that AMPK mice deficient for one of the catalytic alpha subunits displayed reduced endogenous tau phosphorylation. Finally, we found that AMPK deficiency reduced tau pathology in the PS19 mouse model of tauopathy. These results show that AMPK regulates tau phosphorylation in mouse primary neurons as well as in vivo, and thus suggest that AMPK could be a key player in the development of AD pathology.