Omega-3 polyunsaturated fatty acids mitigate working memory decline through feeding a low-carbohydrate and high-protein diet in healthy mice.

Takeru Shima, Daisuke Hirose

Prostaglandins Leukot Essent Fatty Acids

Mar 31, 2026

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Abstract

A low-carbohydrate, high-protein (LC-HP) diet improves metabolic parameters but declines working memory, as shown by reduced hippocampal lipoprotein receptor-related protein 6 (Lrp6) mRNA expression in healthy mice. Omega-3 polyunsaturated fatty acids (n-3 PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), could modulate hippocampal function and Wnt signaling pathway, which is regulated by LRP6 and controls cell proliferation and differentiation. Thus, we hypothesized that intake of n-3 PUFAs alleviates LC-HP diet-induced memory decline. We utilized an LC-HP diet (25.1 % carbohydrate, 57.2 % protein, and 17.7 % fat by caloric content) and a control diet (58.9 % carbohydrate, 24.0 % protein, and 17.1 % fat). Eight-week-old male C57BL/6J mice assigned to six groups: control+vehicle, control+EPA, control+DHA, LC-HP+vehicle, LC-HP+EPA, and LC-HP+DHA. EPA, DHA (0.5 g/kg body weight), or vehicle were administered orally once daily for four weeks. Following the intervention, mice underwent the Y-maze test and hippocampal mRNA analysis. The LC-HP diet declined an alternation rate during Y-maze test, which reflects working memory, n-3 PUFA supplementation enhanced it. Notably, DHA significantly reversed the LC-HP diet-induced downregulation of hippocampal Lrp6 and Dcx mRNA expressions. Although hippocampal Wnt5 mRNA levels were unaffected, hippocampal Lrp6, Wnt5a, and Dcx mRNA levels showed significant positive correlations in LC-HP diet-fed mice (LC-HP+vehicle, LC-HP+EPA, and LC-HP+DHA groups). These findings suggest that n-3 PUFA, particularly DHA, may counteract LC-HP diet-induced memory decline by modulating hippocampal LRP6-related noncanonical Wnt signaling.