Eicosapentaenoic Acid Protects against Metabolic Impairments in the APPswe/PS1dE9 Alzheimer's Disease Mouse Model

Background: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by amyloid-l3 (Al3) plaques. Systemic inflammation and obesity may exacerbate AD pathogenesis. We previously reported anti-inflammatory and anti-obesity effects of EPA in mice. Objectives: We aimed to determine whether EPA reduces obesity-associated metabolic dysfunctions and Al3 accumulation in AD amyloi-dogenic mice. Methods: Two-mo-old APPswe/PS1dE9 transgenic (TG) mice and non-TG littermates were randomly assigned to low fat (LF; 10% kcal fat), high fat (HF; 45% kcal fat), or EPA (36 g/kg)-supplemented HF diets. Body composition, glucose tolerance, and energy expenditure were measured, and serum and brain metabolic markers were tested 38 wk postintervention. Outcomes were statistically analyzed via 3-factor ANOVA, modeling genotype, sex, and diet interactions. Results: HF-fed males gained more weight than females (A = 61 mg; P < 0.001). Compared with LF, HF increased body weights of wild -type (WT) males (A = 31 mg; P < 0.001). EPA reduced HF-induced weight gain in WT males (A = 24 mg; P = 0.054) but not in females. HF mice showed decreased glucose clearance and respiratory energy compared with LF-fed groups (A = -1.31 g/dL; P < 0.001), with no significant effects of EPA. However, EPA conferred metabolic improvements by decreasing serum leptin and insulin (A = -2.51 g/mL and A = -0.694 ng/mL, respectively compared with HF, P < 0.05) and increasing adiponectin (A = 21.6 ng/mL; P < 0.001). As we expected, TG mice expressed higher serum and brain Al3 than WT mice (A = 0.131 ng/mL; P < 0.001 and A = 0.56%; P < 0.01, respectively), and EPA reduced serum Al31-40 in TG males compared with HF (A = 0.053 ng/mL; P < 0.05). Conclusions: To our knowledge, this is the first report that EPA reduces serum Al31-40 in obese AD male mice, warranting further in-vestigations into tissue-specific mechanisms of EPA in AD.