The Effects of Diet Induced Obesity on Central Nervous System Function of APOE Mice

Abstract

APOE4 is the strongest genetic risk factor for Alzheimer’s Disease (AD) and obesity is one of the most common environmental risk factors for AD. With 25% of the population being APOE4 carriers and 40% of the population suffering from obesity, it is important to understand how these two common AD risk factors interact. Here we question how diet induced obesity (DIO) affects the metabolism and central nervous system (CNS) of APOE genotypes, what neurometabolic and neuroinflammatory pathways are involved, and how metformin treatment can reduce the effects of DIO. To test this, we used APOE3 and APOE4 knock-in mice that were placed on high fat diet (HFD, 45% fat) for 12 weeks. HFD increased peripheral metabolic disturbances (weight gain, glucose intolerance, adipose tissue accumulation) in APOE3 and APOE4 mice, with APOE4 mice being more susceptible. HFD also increased neuroinflammation (GFAP and Iba1 immunostaining) and immediate early gene (IEG) expression (c-Fos, Arc) in APOE3 mice, but not in APOE4 mice. Overall, HFD induced metabolic disturbances and resulted in an inflammatory response in the CNS, and these responses were modulated by APOE genotype. To find out whether metformin, a first-line drug for type II diabetes, ameliorated the effects of the HFD, we used APOE3 and APOE4 knock-in mice that were placed on high fat diet (HFD, 45% fat) for 12 weeks and treated with metformin for the last 4 weeks. HFD induced metabolic disturbances in male APOE3 and APOE4 mice, but metformin did not reduce these metabolic disturbances. These metabolic disturbances were not seen in female mice on HFD. Behaviorally, HFD decreased average speed and increased anxiety-like behavior in APOE4 females on the open field test; metformin reduced these effects. HFD also decreased context based freezing behavior in female APOE3 mice, again with a metformin-associated recovery. There were no behavioral effects of HFD on male mice. These studies suggest HFD affects the CNS of APOE3 mice through gliosis and IEG expression, and metformin has the ability to ameliorate behavioral deficits induced by HFD in both female APOE3 and APOE4 mice.