Mechanisms Mediating the Anti‐inflammatory Effects of Eicosapentaenoic Acid in the APPswePS1dE9 Alzheimer's Mouse Model

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a progressive, neurodegenerative disorder characterized by amyloid‐beta (Aβ) plaques, which may be exacerbated by obesity. We previously reported anti‐obesity and anti‐inflammatory effects of eicosapentaenoic acid (EPA), in diet‐induced obese mice. Therefore, the objective of this research is to determine whether EPA also protects against AD‐associated Aβ deposition.MethodMale and female AD mouse model APPswePS1E9 transgenic (TG) and non‐TG wild type littermates (WT) were fed with low fat (LF), high fat (HF), or HF supplemented with 36g/kg EPA (EPA) for 8 months. Mice were metabolically phenotyped during the intervention and blood and tissues were collected at the end of the study. Cortex RNA was isolated, and changes in genes related to AD, obesity, and inflammation were measured. Data were analyzed by 3‐way ANOVA using GraphPad Prism.ResultHF groups weighed significantly more than LF groups (p < 0.001), but other groups were comparable regardless of diet or genotype but overall, males weighed more than females. TG mice had higher serum Aβ‐40 levels than WT mice (p= 0.004), paralleled with higher cortex human APP mRNA levels in TG mice (p = 0.0204). Compared to HF, EPA decreased serum Aβ‐40 in WT male mice (p = 0.0182) as well as APP gene expression in the cortex of male and female TG mice (p = 0.0168 and 0.0030). Moreover, TG mice expressed higher level of MCP1 and IL1β (p = 0.0158 and 0.0142, respectively) mRNA levels compared to WT. Females in both genotypes expressed higher level of MCP1, IL1β and NLRP3 than males (p = 0.0025, 0.0038, and < 0.0001 respectively). In addition, EPA exhibited anti‐inflammatory effects in both sexes of TG mice as indicated by downregulation of mRNAs levels for MCP1 (p = 0.0226 and 0.0108) NLRP3 (p = 0.0205 and < 0.0001) and for IL1β in TG females only (p= 0.0344).ConclusionOur data indicate protective effects of EPA in AD, in part, by reducing Aβ deposition, possibly through inflammatory/neuroinflammatory mechanisms. Given the popularity of fish oil supplements, our findings merit further investigation to dissect mechanisms of fish oil effects especially in AD patients with obesity.