Evaluation of Protective Mechanisms of n-3 PUFA Supplementation on the Aggregation State of Aβ

The available evidence highlights a connection between diminished consumption of omega- 3 polyunsaturated fatty acids (n-3 PUFA) during developmental stages and a greater vulnerability to mood disorders. This study aimed to evaluate the impact of sustained n-3 PUFA deficiency in diet lasting until a crucial moment of neurodevelopment, such as adolescence. Secondly, we tested the effect of n-3 PUFA supplementation on a rodent model exhibiting depressive-like behavior due to prolonged n-3 PUFA deficiency in the diet. Therefore, this study initially employed behavioral and biochemical quantifications in adolescent rats to evaluate potential sex-specific differences in the etiology of anxiety-like disorders related to lifelong n-3 PUFA intake. However, this deficiency resulted in a reduction of cortical serotonin (5-HT) in females, while increased GABA levels were observed in males. Conversely, in the amygdala, 5-HT and noradrenaline (NA) were found to be elevated in rats subjected to a diet lacking in n-3 PUFA. In male rats, a diet deficient in n-3 PUFA resulted in a notable increase in systemic kynurenine levels, while the pro-oxidant metabolite 3- hydroxykynurenine demonstrated higher levels in both sexes. Additionally, considering the recent recognition of the spleen-brain axis in mood disorders and neuroimmune communication, we assessed biomarkers in the spleen. Our results showed that n-3 PUFA deprivation led to a decrease in NA content and an increase in indoleamine 2,3-dioxygenase- 1 expression in females. In contrast, males exhibited higher levels of acetylcholine and tumor necrosis factor alpha. However, the behavioral phenotype was marked by distinct immune activation in male and female rats. In another subset of animals, we exposed female rats to a diet high in n-3 PUFA after long-life exposure to its deficiency. We found that, n-3 PUFA supplementation improved behavioral and neurochemical deficits by normalizing neurotransmitter levels. The expression of nerve growth factor (NGF) in the prefrontal cortex (PFC) and brain-derived neurotrophic factor (BDNF) in the PFC and hippocampus (HIPP) were significantly increased, suggesting that this supplementation enhances synaptic plasticity. However, Amyloid oligomers and Amyloid-beta precursor protein (APP) levels, involved in neurodegenerative processes, were only partially recovered, while supplementation restored synaptophysin levels and improved calmodulin-dependent protein kinase II levels in the PFC. Finally, n-3 PUFA replenishment reduced plasma levels of 3- hydroxykynurenine, a pro-oxidant metabolite of the tryptophan/kynurenine pathway, but could not restore 5-HT and the Kynurenine/tryptophan ratio (KTR). In conclusion, our findings support the hypothesis that reintroducing n-3 PUFA during a late stage of development can offer significant benefits to the central nervous system. It is crucial to recognize the importance of addressing N-3 PUFA deficiency in the maternal diet and/or during the postnatal period, as some neurotoxic effects may not be entirely reversible.