AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism.

Elsa M Janle,Pallavi Chandakkar,Peter Davies,James E Simon,Jessica Lobo,Philippe Marambaud,Qingli Wu,Haitian Zhao,Mario G Ferruzzi,Luca Giliberto,Valérie Vingtdeux

doi:10.1074/jbc.m109.060061

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.

Highlights

Alzheimer disease (AD)2 is a progressive neurodegenerative disorder and the first cause of dementia
Resveratrol did not noticeably affect the steady state levels of full-length amyloid-␤ precursor protein (APP) or APP C-terminal fragments (Ref. 8 and supplemental Fig. S1), showing that resveratrol reduced A␤ levels without affecting APP processing
These results indicate that one of the primary effects of resveratrol is to target AMPK to increase its phosphorylation at Thr-172 and to promote its activation, as demonstrated by the increased phosphorylation of acetylCoA carboxylase (ACC) and CREB upon resveratrol treatment

Summary

Introduction

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the first cause of dementia. 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]. 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. AMPK is a Ser/Thr protein kinase formed by a heterotrimeric complex comprising a catalytic ␣ subunit and regulatory ␤ and ␥ subunits. AMPK is activated by different upstream kinases via phosphorylation within its activation loop at Thr172 [14, 15]. The main AMPK-activating kinase is LKB1, a protein expressed ubiquitously and recruited for AMPK phosphorylation after an elevation of the AMP/ATP ratio.

Methods

Results

Conclusion