Endogenous Conversion of Omega-6 into Omega-3 Fatty Acids Improves Neuropathology in an Animal Model of Alzheimer's Disease

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) reduces amyloid-beta (A beta) and tau pathology and improves cognitive performance in animal models of Alzheimer's disease (AD). To exclude confounding variables associated with the diet, we crossed 3xTg-AD mice (modeling AD neuropathology) with transgenic Fat-1 mice that express the fat-1 gene encoding a PUFA desaturase, which endogenously produces n-3 PUFA from n-6 PUFA. The expression of fat-1 shifted the n-3:n-6 PUFA ratio upward in the brain (+11%, p < 0.001), including docosahexaenoic acid (DHA; +5%, p < 0.001) in 20 month-old mice. The expression of fat-1 decreased the levels of soluble A beta(42) (-41%, p < 0.01) at 20 months without reducing the level of insoluble forms of A beta(40) and A beta(42) in the brain of 3xTg-AD mice. The 3xTg-AD/Fat-1 mice exhibited lower cortical levels of both soluble (-25%, p < 0.05) and insoluble phosphorylated tau (-55%, p < 0.05) compared to 3xTg-AD mice, but only in 20 month-old animals. Whereas a decrease of calcium/calmodulin-dependent protein kinase II was observed in 3xTg-AD/Fat-1 mice (-39%, p < 0.05), altered tau phosphorylation could not be related to changes in glycogen synthase kinase 3 beta, cyclin-dependent kinase 5, or protein phosphatase type 2A enzymatic activity. In addition, the expression of the fat-1 transgene prevented the increase of glial fibrillary acidic protein (-37%, p < 0.01) observed in 20 month-old 3xTg-AD mice. In conclusion, the expression of fat-1 in 3xTg-AD mice increases brain DHA and induces biomarker changes that are consistent with a beneficial effect against an AD-like neuropathology.