Folic acid combined with DHA ameliorates cognitive function via modulating microglia-mediated neuroimmune

It remains unclear whether folic acid (FA) and docosahexaenoic acid (DHA) could improve cognitive performance by regulating microglia-mediated neuroimmune mechanisms. This study aimed to reveal the underlying mechanisms of FA and DHA supplementation in improving the cognitive performance. A randomized controlled trial was conducted in elderly patients with mild cognitive impairment (MCI) to examine the impact of FA (800 μg/day) and DHA (1.2 g/day) on cognitive functions and neuroimmune-related inflammatory cytokines, such as interleukin (IL)-18, IL-1β, IL-17, IL-21, IL-2, and IL-15. Besides, it was further explored whether FA and DHA may enhance cognitive performance by modifying neuroimmune and microglia in Alzheimer’s disease (AD) inflammation mice. Our results found that FA and/or DHA improved cognitive performance and decreased the level of inflammatory cytokines in MCI patients and AD inflammation mice. The combined intervention was more effective than the FA or DHA intervention alone. Meanwhile, FA and/or DHA inhibited the microglia activation and modulated the microglia phenotype, manifested as an increased level of the M2 phenotype and a decreased level of the M1 phenotype. Additionally, the combined intervention with FA and DHA reduced the concentration of C-C motif chemokine ligand 2, C-C motif chemokine receptor 2, and CD8⁺ T cells in brain, but increased the coverage of neurons. More importantly, after microglial depletion using PLX5622, the combined intervention with FA and DHA further improved cognitive performance and reduced the level of inflammatory cytokines. These findings provide compelling evidence that FA and DHA are expected to constitute a promising nutritional intervention strategy for preventing the development of AD by restoring neuroimmune homeostasis through microglial modulation.