TREM2 promotes hippocampal neurogenesis through regulating microglial M2 polarization in APP/PS1 mice

Triggering receptor expressed on myeloid cells-2 (TREM2) mainly expressed on microglia in the brain, and its mutations can increase the risk of Alzheimer's disease (AD). Upregulation or activation of TREM2 has been found to ameliorate several pathological features of AD, such as the reduction of amyloid beta (Aβ) plaques and tau hyperphosphorylation. However, the effects of TREM2 on neurogenesis are little understood. Here, we aimed to investigate the effects of TREM2 on hippocampal neurogenesis associated with microglial M2 polarization in APP/PS1 mice. Lentivirus vectors were used to interfere with the expression of TREM2 on microglia in the hippocampus of APP/PS1 mice and BV2 cells. The supernatant was collected from BV2 cells as a conditioned medium (CM) to culture neural stem cells (NSCs) in vitro. Upregulation of TREM2 partially salvaged the proliferation of NSCs and the decrease of the number of immature/mature neurons in the hippocampus of APP/PS1 mice, which was accompanied by an improvement in cognitive ability. Furthermore, upregulation of TREM2 increased the M2 microglia marker CD206, brain-derived neurotrophic factor (BDNF), and anti-inflammatory factors, while decreased the M1 microglia markers CD16/32 and CD86 and pro-inflammatory factors in vivo and in vitro. Importantly, the upregulation of TREM2 also led to a significant increase in the phosphorylation of PI3K and Akt. In vitro, treatment with LY294002, a PI3K inhibitor, abolished the beneficial effects of TREM2 on shifting microglia from M1 to M2 and the proliferation and differentiation of NSCs. Taken together, these findings indicated that upregulation of TREM2 activated the PI3K/Akt signaling pathway to promote microglial M2 polarization and led to the secretion of more BDNF, accompanied by an improved hippocampal neurogenesis and spatial cognitive function in APP/PS1 mice. Thus, TREM2 might be a promising target for the treatment of neurodegenerative disease.