The effects of omega-3 fatty acid deficiency during development on oxidative fatty acid degradation during maturity in a mouse model of Alzheimer's disease

Abstract

Metabolic conditions during brain development may have long-term consequences on brain metabolism, thereby influencing the risk of neurodegenerative disease in later life. To ascertain the long-term consequences of ω3 fatty acid deficiency during brain development on oxidative fatty acid degradation in the brain and the development of Alzheimer-like pathology, wild-type (WT) female mice were fed diets that were either replete or deficient in ω3 fatty acids for five weeks. These females were then mated with hemizygous 5xFAD male transgenic (TG) mouse models of Alzheimer's disease (AD), and the progeny were continued on diets that were either ω3-replete or ω3-deficient. When the progeny were six months of age, they received radiolabeled arachidonic acid (ARA) by intracerebroventricular injection. Five days after these injections, the brains were harvested and oxidative degradation of the radiolabeled ARA was characterized. Among the progeny of female mice on an ω3-replete diet, TG progeny had lower PSD-95 expression, and higher oxidative ARA degradation, than WT progeny. Progeny on an ω3-deficient diet, however, had no significant differences in PSD-95 expression between TG and WT mice, or in the extent of ARA degradation. In TG mice, an ω3-deficient diet reduced oxidative ARA degradation to a greater extent than in WT mice. The reductions in oxidative ARA degradation occurred even if the progeny of female mice on an ω3-deficient diet resumed an ω3-replete diet immediately upon weaning. These results demonstrate that dietary ω3 fatty acid deficiency during development can cause long-term changes in the expression of a synaptic marker, and long-term reductions in the rate of ARA degradation in the WT brain, that are not completely alleviated by an ω3-replete diet after weaning. The elimination of differences between TG and WT mice by an ω3-deficient diet suggest that mechanisms regulating PSD-95 expression and the oxidative degradation of ARA are related, and that the timing of dietary ω3 intake during development may influence AD-related pathological changes later in life.

Free Radical Chain Reactions and Polyunsaturated Fatty Acids in Brain Lipids

“…These experiments were prompted by previously reported in vivo results showing that a dietary omega-3-deficiency led to significantly lower rates of in vivo ARA degradation in mouse brain . This reduction might be explained in light of the results reported herein by reduced free radical chain reactions under conditions of omega-3 PUFA deficiency.…”

“…Paradoxically, however, a diet-induced deficiency of ω3 PUFAs reduces the in vivo oxidative degradation of ARA in the brains of mice. 9 …”

“…Because most PUFAs in the brain are either arachidonate (ARA, ω3) or docosahexaenoate (DHA, ω6), it follows that a decrease in the concentration of one of these PUFA species should reduce the number of reactions between this PUFA species and the available • OH radicals, making more • OH radicals available to increase the oxidatively degradation of the other PUFA species. Paradoxically, however, a diet-induced deficiency of ω3 PUFAs reduces the in vivo oxidative degradation of ARA in the brains of mice …”

“…Because most PUFAs in the brain are either arachidonate (ARA, ω3) or docosahexaenoate (DHA, ω6), it follows that a decrease in the concentration of one of these PUFA species should reduce the number of reactions between this PUFA species and the Paradoxically, however, a diet-induced deficiency of ω3 PUFAs reduces the in vivo oxidative degradation of ARA in the brains of mice. 9 This paradox may be resolved if a significant amount of oxidative damage is caused by free radical chain reactions, also known as autoxidation (Figure 1A). In chain reactions, the extent of chemical damage will vary with the concentration of reactants; increasing the concentration of a reactant increases the efficiency of a chain reaction by shortening the diffusion distances between reacting molecules.…”

Natural Bioactive Molecules as Neuromedicines for the Treatment/Prevention of Neurodegenerative Diseases

“…The results indicated that dietary ω-3 FA deficiency during brain development can induce long-term changes in the synaptic marker expression and long-term reductions in the rate of arachidonic acid (AA) degradation in the mouse brain, which are not entirely alleviated by ω-3-enriched diet after weaning. The elimination of differences between transgenic and wild-type mice by an ω-3-deficient diet suggests that mechanisms regulating PSD-95 expression and the oxidative degradation of AA are related and that the timing of dietary ω-3 intake during development may influence AD-related pathological changes later in life …”