Synergistic effect of APOE genotype and obesity in CNS inflammation and risk of Alzheimer's disease

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PROJECT SUMMARY We have previously pursued the hypothesis that APOE genotype alters normal brain neurochemistry and structure early in life, generating an environment that alters the risk of Alzheimer’s Disease (AD) with aging. Studies with APOE knock-in mice have demonstrated that APOE genotype affects neuroinflammation in response to various neurological injuries in an isoform-specific manner, with apoE4 displaying the least anti- inflammatory activity. Inflammation is also a consequence of several environmental risk factors for AD, such as traumatic brain injury, obesity, and metabolic syndrome. Obesity is the strongest environmental risk factor for AD. With 14% of the US population being APOE4 carriers and 35% of the population suffering from obesity, it is extremely important to understand how these two common AD risk factors synergize. Sex is also a critical variable in the risk of cognitive impairments, with females at significantly higher risk. Thus, the risk of AD depends on a complex set of connections between genetic, environmental, and sex effects. This project aims to analyze these interactions in healthy rodent models, thus providing early disease targets that could be use as markers of AD risk and as targets for disease intervention. Aim 1 will determine robust markers of neuroinflammation in APOE3 and APOE4 male and female mice after experiencing chronic peripheral inflammation induced by diet. We will test our hypothesis that specific neuroinflammatory pathways will be coordinately affected by these three AD risk factors. We have begun to identify neuroinflammatory pathways through non-directed transcript analysis, and we will test the rigor of those findings through qPCR. We will further refine specific neuroinflammatory pathways using immunofluorescence, in situ hybridization analyses, and kinase measures. Finally, we will define inflammatory cell responses by defining the density, morphology, and motility of the microglia using our model of CX3CR1GFP/+ mice on APOE3 and APOE4 knock-in backgrounds. Aim 2 will determine the effects of two safe, anti-inflammatory drugs on CNS inflammation markers in the subgroups of most affected APOE female and male mice. We will treat APOE3 and APOE4 mice on a high fat diet with metformin (a diabetes treatment) or 4F peptide (promoting high density lipoproteins). We will test our hypothesis that safe anti-inflammatory drugs could reduce the neuroinflammatory pathways most consistent with AD risk factors. These studies will refine the pathways identified in Aim 1, and further those findings by addressing whether there are functional CNS consequences of these treatments through behavioral assays. Furthermore, we will test whether any inflammation pathways identified in CNS correlate with effects in the blood using assays on plasma samples. By the end of this R21 study, we will have identified a subset of neuroinflammatory molecules that could be use as early markers of AD risk and defined whether anti- inflammatory approaches will be useful in personalized medicine approaches taking APOE genotype, diet, and sex into account.