Metabolic and Central Effects of High Fat Diet and Fish Oil in an Amyloidogenic Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive, age-related neurodegenerative disease characterized by amyloid-beta(Aβ) plaques and phosphorylated tau tangles, may be exacerbated by chronic neuroinflammation drives from obesity. Thus, we studied Eicosapentaenoic acid (EPA) with anti-inflammatory effects added to high fat (HF) diet would regulate metabolic and inflammatory pathways related to AD through target genes, mediating anti-inflammatory and anti-obesity effects in an obesity induced mouse model of AD. APPswePS1E9 transgenic (TG) and non-TG littermates (WT), male and female fed with low fat (LF), high fat (HF), or HF supplemented with EPA (EPA) for 8 months. Body weight and metabolic data recorded during the intervention. Blood and tissues were collected at the end of the intervention. Serum Aβ-40 levels were measured by immune-multiplexing. Brain’s left cortex were used to RNA isolation and specific gene expression related to AD, obesity, and inflammation were assessed by quantitative polymerase chain reaction (QPCR) and RNA sequencing. On average TG mice BW were not different from WT mice. TG groups had higher had higher Aβ-40 (p < 0.05) vs. WT mice the same as human APP gene expression (p = 0.0204). Inflammatory gene such as MCP1 and IL1β were higher in TG mice compared to WT (p = 0.0158 and p = 0.0142, respectively). On average male had higher BW (p < 0.001) and female had higher inflammatory gene expression such as MCP1. IL1β and NLRP3 (p = 0.0025 and p = 0.0038, p < 0.0001 respectively). Interestingly compared to HF diet EPA decreased Aβ-40 in TG male mice (p = 0.0182) in serum and this data confirmed by human APP gene expression (p = 0.0168) same in females APP expression was higher in HF TG compared to EPA fed TG group (p = 0.0030). EPA compared to HF diet decreased inflammatory genes such as IL1β in TG females (p = 0.0344), and in TG male and female MCP1 (p = 0.0226 and p = 0.0108) and NLRP3 (p = 0.0205 and p < 0.0001) were reduced. Overall, this data reveals genotypic and sex differences in inflammatory response and possible effect of dietary EPA intervention in protecting against AD pathology. These targets merit further investigation to better understand the protective mechanisms of EPA in obesity-associated AD.

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