Physical activity has been considered an important non-medication intervention in preserving mnemonic processes during aging. However, how aerobic exercise promotes such benefits for human health remains unclear. In this study, we aimed to explore the neuroprotective and anti-inflammatory effects of aerobic exercise against lipopolysaccharide (LPS)-induced amnesic C57BL/6J mice and BV-2 microglial cell models. In the in vivo experiment, the aerobic exercise training groups were allowed to run on a motorized treadmill 5 days/week for 4 weeks at a speed of 10 rpm/min, with LPS (0.1 mg/kg) intraperitoneally injected once a week for 4 weeks. We found that aerobic exercise ameliorated memory impairment and cognitive deficits among the amnesic mice. Correspondingly, aerobic exercise significantly increased the protein expressions of FNDC5, which activates target neuroprotective markers BDNF and CREB, and antioxidant markers Nrf2/HO-1, leading to inhibiting microglial-mediated neuroinflammation and reduced the expression of BACE-1 in the hippocampus and cerebral cortex of amnesic mice. We estimated that aerobic exercise inhibited neuroinflammation in part through the action of FNDC5/irisin on microglial cells. Therefore, we explored the anti-inflammatory effects of irisin on LPS-stimulated BV-2 microglial cells. In the in vitro experiment, irisin treatment blocked NF-κB/MAPK/IRF3 signaling activation concomitantly with the significantly lowered levels of the LPS-induced iNOS and COX-2 elevations and promotes the Nrf2/HO-1 expression in the LPS-stimulated BV-2 microglial cells. Together, our findings suggest that aerobic exercise can improve the spatial learning ability and cognitive functions of LPS-treated mice by inhibiting microglia-mediated neuroinflammation through its effect on the expression of BDNF/FNDC5/irisin.
