Protective effects of eicosapentaenoic acid on metabolic features and cognitive function in the APPswePS1dE9 Alzheimer’s mouse model

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterized by amyloid‐beta (Aβ) plaque deposition and may be exacerbated by aging‐induced neuroinflammation and obesity. We hypothesized that compared to high fat (HF) diets, FO with anti‐inflammatory and anti‐obesity properties, would reduce metabolic and cognitive dysfunctions in an AD amyloidogenic mouse model of obesity.MethodTwo‐month‐old, both sexes, APPswePS1E9 transgenic (TG) and non‐TG littermates were randomly assigned and fed low fat (LF), HF, or HF supplemented with FO for eight months (n=8‐10/group). Body weight and food intake were recorded weekly, and body composition was measured bi‐monthly. Glucose Tolerance Test (GTT) and Morris water maze (MWM) were measures at 5‐ and 9‐ months, respectively. At termination, blood and tissues were collected. Serum Aβ‐40 levels were measured by immune‐multiplexing. Missing data were imputed via multiple imputations. Outcomes were analyzed in three‐way ANOVA, modeling genotype interactions, sex and diet, and subsequent Tukey‐corrected pair‐wise comparisons using R (version 4.0.2).ResultOn average, fat mass (FM) of non‐TG mice did not differ from TG mice. However, TG mice ate more (p < 0.001), trended towards lower glucose clearance (p = 0.066) and had higher Aβ‐40 (p < 0.05) vs. non‐TG mice. On average, male were fatter (p < 0.001) and more glucose intolerant compared to female mice (p < 0.001), yet there were no sex differences for Aβ‐40 (p = 0.8718). On average, LF diet decreased final FM and improved GTT vs. HF and FO diets (p < 0.001); however, adiposity and GTT were not different between FO and HF fed mice. Interestingly, compared to HF, FO decreased serum Aβ‐40 in TG male mice (p = 0.0182), but not among TG female or non‐TG mice. This unique between‐group difference was not apparent for FM or GTT. In MWM test, HF non‐TG mice found the platform faster than TG mice (p = 0.037).ConclusionOverall, LF diets conferred metabolic improvements over HF diets, while long term supplementation of FO to HF diets had limited metabolic and cognitive benefits. Interestingly, FO reduction of serum Aβ‐40 in AD mice merits further investigation.