Resveratrol and Metformin Recover Prefrontal Cortex AMPK Activation in Diet-Induced Obese Mice but Reduce BDNF and Synaptophysin Protein Content.

Background: Obesity, insulin resistance, and type 2 diabetes are established risk factors for the development of Alzheimer's disease (AD). Given this connection, two drugs, metformin (MET) and resveratrol (RESV), are considered for the clearance of amyloid-β peptides through AMPK-mediated activation of autophagy. However, overactivation of AMPK observed in late-stage AD brains and relationships between AMPK and neurogenesis (through mTORC1 inhibition), questions treatment with these drugs.

Objective: To examine if MET and/or RESV supplementation activates brain AMPK, regulates markers of autophagy, and affects markers of neuronal health/neurogenesis.

Methods: 8-week-old male C57BL/6J mice were fed a low (N = 12; 10% kcal fat; LFD) or high fat diet (N = 40; 60% kcal fat; HFD) for 9 weeks to induce insulin resistance and obesity. HFD mice were then treated with/without MET (250 mg/kg/day), RESV (100 mg/kg/day), or COMBO (MET: 250 mg/kg/day, RESV: 100 mg/kg/day) for 5 weeks. Hippocampus and prefrontal cortex were extracted for western blotting analysis.

Results: Cortex AMPK (T172) and raptor (S792, the regulatory subunit of mTORC1) phosphorylation were upregulated following RESV, COMBO treatments. mTOR (S2448) and ULK1 (S555) activation was seen following MET, COMBO and RESV, COMBO treatments, respectively, in the cortex and hippocampus. p62 content was decreased following RESV, COMBO, with LC3 content being increased following RESV treatment in the cortex. Brain derived neurotropic factor (BDNF) was significantly decreased following RESV, COMBO, and synaptophysin following all treatment in the cortex.

Conclusion: These results demonstrate that while treatments upregulated markers of autophagy in the prefrontal cortex, reductions in neuronal health markers question the efficacy of AMPK as a therapy for AD.