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

Abstract

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.

Apolipoprotein ε4 modifies obesity-related atrophy in the hippocampal formation of cognitively healthy adults

“…The precise nature of these complex synergistic effects between obesity and APOE ε4 remain elusive and require further investigation. A recent animal study ( Jones et al., 2021 ) points to inflammation and neuronal plasticity mechanisms underpinning interaction effects between obesity and APOE genotype. In this study, a high-fat diet increased gliosis and immediate-early gene expression only in APOE ε3 but not APOE ε4 knock-in mice.…”

Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer’s Disease-Relevant Phenotypes in Mice

“…For instance, a study showed a diet-induced myelin breakdown in aging B6 mice that were dependent on the complement cascade (Graham et al, 2020). Also, the addition of an HFD exacerbated AD phenotypes in mouse models relevant to early-onset AD (Knight et al, 2014;Jones et al, 2019;Bracko et al, 2020;Robison et al, 2020;Jones et al, 2021). In one study, Jones et al (2019) found that with HFD, male APOE4 mice were more susceptible to metabolic disturbances, including glucose intolerance when compared to APOE3 mice.…”

“…Behavioral deficits were not observed due to HFD, suggesting that metabolic responses to HFD are dependent on both sex and APOE genotype. A second study concluded that early dysregulation of inflammation in APOE4 brains could predispose to CNS damage from various insults, including diet, and later results in the increased CNS damage normally associated with the APOE4 genotype (Jones et al, 2021). However, the effects of a western-like diet in the context of multiple genetic risk factors for LOAD have not been studied.…”

Plcg2M28Linteracts with high fat-high sugar diet to accelerate Alzheimer’s disease-relevant phenotypes in mice

“…Behavioral deficits were not observed due to the HFD, suggesting metabolic responses to HFD are dependent on both sex and APOE genotype. A second study concluded that early dysregulation of inflammation in APOE4 brains could predispose to CNS damages from various insults, including diet, and later result in the increased CNS damage normally associated with the APOE4 genotype [25]. However, the effects of a western-like diet in the context of multiple genetic risk factors for LOAD have not been studied.…”

“…For instance, one study showed diet-induced myelin breakdown in aging B6 mice that was dependent on the complement cascade [20]. Also, the addition of a HFD exacerbated AD phenotypes in mouse models relevant to early-onset AD [21][22][23][24][25]. In one study, Jones et al [24] found that with HFD, male APOE4 mice were more susceptible to metabolic disturbances, including glucose intolerance when compared to APOE3 mice.…”