Protective Effects of Eicosapentaenoic Acid on Adiposity and Amyloidogenic Features in the APPswePS1dE9 Alzheimer’s Mouse Model

Abstract

ObjectivesAlzheimer’s disease (AD) is a degenerative brain disease characterized by atypical development of amyloid-beta (Aβ) plaques. We previously showed that eicosapentaenoic acid (EPA), found in fish oil exerted anti-obesity and anti-inflammatory effects in diet-induced obese (DIO) mice. Here we hypothesize that EPA will reduce both adiposity and neuroinflammation in an amyloidogenic Alzheimer’s DIO mouse model. MethodsTwo-month-old male and female APPswePS1E9 transgenic (TG) and non-TG littermates were randomly assigned to low fat (LF; 10% kcal fat), high fat (HF; 45% kcal fat), or HF supplemented with EPA (36 g/kg EPA) diets for eight months. Body weights were recorded weekly, blood and tissues were harvested at termination. Serum amyloid Aβ-40 (AD marker), leptin, adiponectin, and resistin (adiposity markers) levels were quantified by Multiplex assays (n = 6–7/group). Outcomes were analyzed in three-way ANOVA, modeling genotype interactions, sex, and diet, using GraphPad (Version 9.0.1). ResultsOn average, TG mice had higher Aβ-40 in serum (p < 0.05) compared to non-TG mice in both males and females; Aβ-40 concentration did not differ by sex. However, serum leptin and resistin were higher in males vs. females (p < 0.001). Adiponectin did not differ by sex (P = 0.1897) and no adipokine differed by genotype. Interestingly, in TG males, compared to HF, EPA decreased serum Aβ-40, leptin, and resistin (P = 0.0182, P = 0.0086, P = 0.0051 respectively). Moreover, in non-TG male mice, EPA increased serum adiponectin compared to HF (P = 0.0342) and no other interactions were significant. ConclusionsEPA reduced adiposity, resistin, and serum Aβ-40 in HF-fed TG male mice. Additional analyses in the brain and adipose tissues from these mice are ongoing. These findings warrant future studies in humans to determine whether consumption of high doses of fish oil, known to reduce hypertriglyceridemia, may benefit patients with AD and whether there are sex differences in response to fish oil. Funding SourcesNIH (NCCIH and NIA) grant #R15AT008879–01A1.