The role of dysregulation of glial cells in ageing-associated memory impairment: different effects of omega-3 polyunsaturated fatty acid EPA and DHA treatments

Ageing-related structural and functional changes are accompanied by polarized imbalance of microglia and astroglia, which enhance neuroinflammation and neurodegeneration. As indispensable components of brain membranes, omega (n)-3 polyunsaturated fatty acids (PUFAs) are parallelly reduced in ageing. However, conflict results have been reported after mixed n-3 PUFA treatments. Thus, this study explored the role of glial phenotypes in ageing-induced memory impairment and compared therapeutic effects of DHA and EPA. Cognitive and spontaneous behaviors were tested in Morris Water Maze (MWM) and "open field". Then n-3 PUFA profile, glial phenotype markers, and synaptic protein PSD-95 were detected. The results revealed that ageing rats showed memory impairment in MWM, which was improved by both PUFAs, while more effective for DHA than EPA. The imbalance between microglial M1/M2 polarizations, such as up-regulating IBA1, and down-regulating CD206 and ARG-1 were reversed by both n-3 PUFA, while DHA effect on CD206 was better. Similarly, the activation of astrocyte A1 polarization presented increasing S100B and C3, but decreasing S100a10 in ageing rat, which were attenuated by both PUFAs, while DHA was better restored the A2 S100a10 than EPA. Consistently with M1 and A1 activation in ageing rats, the concentration of proinflammatory cytokines TNF-α, interleukin (IL)-1β and IL-6 were significantly elevated accompanied by increasing TLR4 and NLRP3 inflammasome production, while DHA attenuated most cytokine changes, but EPA only suppressed IL-6. In addition, brain-derived neurotrophic factor (BDNF) was decreased in aged rats with increasing pro-BDNF, which was more powerfully down-regulated by DHA than EPA. DHA or EPA supplement increased the DHA or EPA respectively and balanced the n-6/n-3 ratio in the brain. Moreover, ageing decreased the nicotinic acetylcholine receptor (nAChR) β2 and synaptic protein PSD-95 were improved by both, but DHA was better again. In summary, enhanced microglial M1/M2 and astrocytic A1/A2 polarizations may contribute to increased proinflammatory cytokines and dysfunction of BDNF system. DHA was more effective than EPA on alleviating ageing-associated meory impairment.