Differential impact of eicosapentaenoic acid and docosahexaenoic acid in an animal model of Alzheimer's disease.

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) improves cognitive performance in several animal models of Alzheimer's disease (AD), an effect often associated with reduced amyloid-beta (Aβ) and/or tau pathologies. However, it remains unclear to what extent eicosapentaenoic (EPA) provides additional benefits compared to docosahexaenoic acid (DHA). Here, male and female 3xTg-AD mice were fed for 3 months (13 to 16 months of age) the following diets: (1) control (no DHA/EPA), (2) DHA (1.1g/kg) and low EPA (0.4g/kg), or (3) DHA (0.9g/kg) with high EPA (9.2g/kg). The DHA and DHA+EPA diets respectively increased DHA by 19% and 8% in the frontal cortex of 3xTg-AD mice, compared to controls. Levels of EPA, which were below the detection limit after the control diet, reached 0.14% and 0.29% of total brain fatty acids after the DHA and DHA+EPA diet, respectively. DHA and DHA+EPA diets lowered brain arachidonic acid (ARA) levels and the n-6:n-3 docosapentaenoic acid (DPA) ratio. Brain uptake of free ¹⁴C-DHA measured through intracarotid brain perfusion, but not of ¹⁴C-EPA, was lower in 3xTg-AD compared to NonTg mice. DHA and DHA+EPA diets in 3xTg-AD mice reduced cortical soluble phosphorylated tau (pS202) (-34% high-DHA, -34% DHA+EPA, p<0.05) while increasing p21 activated kinase (+58% and +83%, p<0.001; respectively). High EPA intake lowered insoluble phosphorylated tau (-31% versus DHA, p<0.05). No diet effect on Aβ levels was observed. In conclusion, dietary intake of DHA and EPA leads to differential changes in brain PUFA while altering cerebral biomarkers consistent with beneficial effects against AD-like neuropathology.