High-fat diet increases gliosis and immediate early gene expression in APOE3 mice, but not APOE4 mice.

BACKGROUND: APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD), and obesity is a strong environmental risk factor for AD. These factors result in multiple central nervous system (CNS) disturbances and significantly increase chances of AD. Since over 20% of the US population carry the APOE4 allele and over 40% are obese, it is important to understand how these risk factors interact to affect neurons and glia in the CNS. METHODS: We fed male and female APOE3 and APOE4 knock-in mice a high-fat diet (HFD-45% kcal fat) or a "control" diet (CD-10% kcal fat) for 12 weeks beginning at 6 months of age. At the end of the 12 weeks, brains were collected and analyzed for gliosis, neuroinflammatory genes, and neuronal integrity. RESULTS: APOE3 mice on HFD, but not APOE4 mice, experienced increases in gliosis as measured by GFAP and Iba1 immunostaining. APOE4 mice on HFD showed a stronger increase in the expression of Adora2a than APOE3 mice. Finally, APOE3 mice on HFD, but not APOE4 mice, also showed increased neuronal expression of immediate early genes cFos and Arc. CONCLUSIONS: These findings demonstrate that APOE genotype and obesity interact in their effects on important processes particularly related to inflammation and neuronal plasticity in the CNS. During the early stages of obesity, the APOE3 genotype modulates a response to HFD while the APOE4 genotype does not. This supports a model where early dysregulation of inflammation in APOE4 brains could predispose to CNS damages from various insults and later result in the increased CNS damage normally associated with the APOE4 genotype.

Metabolic Disturbances of a High-Fat Diet Are Dependent on APOE Genotype and Sex.

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD). APOE4 is also associated with an increased risk of metabolic syndrome. Obesity is a major environmental risk factor for AD. While APOE genotype and obesity independently affect metabolism and cognition, they may also have synergistic effects. Here, we examined the metabolic and behavioral alterations associated with a high-fat diet (HFD) in male and female APOE knock-in mice. Male and female mice were fed a 45% kcal HFD or a 10% kcal low-fat diet (LFD) for 12 weeks and adipose tissue accumulation, glucose levels, anxiety-like behavior, and spatial memory were examined. We found that with HFD, male APOE4 mice were more susceptible to metabolic disturbances, including visceral adipose tissue (VAT) accumulation and glucose intolerance when compared to APOE3 mice, while female APOE3 and APOE4 mice had similar metabolic responses. Behaviorally, there were no effects of HFD in mice of either genotype. Our results suggest that metabolic responses to HFD are dependent on both sex and APOE genotype.