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

Abstract

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) reduces amyloid-β (Aβ) 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 3 × Tg-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 Aβ₄₂ (-41%, p < 0.01) at 20 months without reducing the level of insoluble forms of Aβ₄₀ and Aβ₄₂ in the brain of 3 × Tg-AD mice. The 3 × Tg-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 3 × Tg-AD mice, but only in 20 month-old animals. Whereas a decrease of calcium/calmodulin-dependent protein kinase II was observed in 3 × Tg-AD/Fat-1 mice (-039%, p < 0.05), altered tau phosphorylation could not be related to changes in glycogen synthase kinase 3β, 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 3 × Tg-AD mice. In conclusion, the expression of fat-1 in 3 × Tg-AD mice increases brain DHA and induces biomarker changes that are consistent with a beneficial effect against an AD-like neuropathology.

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

“…The ratio of positive PHF-stained cells was 0/100 for control, 18/100 for repeat-blast, and 3/100 for repeatblast+DHA animals (chi-square test 26.571 with 2 degrees of freedom, p < 0.0001). The ratio of positive CP-13-stained cells for controls was 0/100, for repeat blast it was 17/100, and for repeat-blast+DHA it was 4/100 (chi-square test 22.571 with 2 degrees of freedom, p < 0.0001). In addition, H & E staining revealed a heterogeneous appearance, chromatolysis, vacuolization, and degenerating neurons 3 weeks after repetitive blasts but not in control or repeatblast+DHA animals ( Fig.…”

“…In addition, DHA has recently been shown to readily enter the brain and inhibit neurofibrillary tangle formation in a murine model of Alzheimer's disease. 13,22 Linking these two important properties of DHA is a topic of ongoing investigation.…”

Relevância dos Índices Ómega-3 e Razão Ómega-6 / Ómega-3 na Prevenção do Défice Cognitivo

“…52 Outros estudos em humanos e animais suportam a noção de que a razão n-6 / n-3 está associada com risco de demência e declínio cognitivo, e o menor consumo de n-3 poderá acelerar entre 10% e 80% o declínio cognitivo. [19][20][21][22][23][24] Nunes B, et al Ómega-3, razão ómega-6 / ómega-3 e função cognitiva, Acta Med Port 2017 Mar;30(3):213-223 Tabela 5 -Associação entre o índice ómega-3 e a razão ómega-6 / ómega 3 e compromisso em domínios específicos…”

Lipid metabolism in Alzheimer’s disease

“…In addition, overexpression of Fat-1, enhancing endogenous production of n-3 PUFAs, in 3×Tg-AD mice significantly reduces phosphorylated tau and improves brain function [106] . Although the reasons for these disparities are unclear, it is probable that different stages of AD have different effects on fatty-acid metabolism, or gene expression for fatty-acid synthesis differs during different stages.…”

“…However, recent in vivo studies using an APP mutant AD mouse model showed that both extraneously supplied and endogenous PUFAs suppress Aβ production and the formation of amyloid plaques [106] . Similarly, MUFAs, mainly oleic acid, inhibit the production of Aβ and amyloid plaque formation both in vitro and in vivo [90] .…”