Dissecting The Roles Of Soluble TREM2 In The Pathogenesis Of Alzheimer’s Disease

Variants in the Triggering receptor expressed on myeloid cell 2(TREM2)is recently reported to be associated with the risk for Alzheimer disease(AD),with R47H increasing the risk for AD with an odds ratio similar to that of carrying an apolipoprotein E ε4 allele.In the central nervous system,microglia are the only cells that express TREM2.The levels of a proteolytic product of TREM2,soluble TREM2(sTREM2),are elevated in cerebrospinal fluid(CSF)of AD patients and correlated with AD progression.It is also found that the CSF levels of sTREM2 are positively correlated with the levels of neuronal injury markers including phosphorylated Tau and total Tau.These findings suggest that sTREM2 may be involved in AD pathologenesis.To explore the effects of sTREM2 on the pathological hallmarks of AD,we delivered the recombinant sTREM2 protein into the hippocampus of 5xFAD mice by stereotaxic injection method.Our results show that sTREM2 significantly reduces Aβplaque deposition and increases the number of plaque-associated microglia.Importantly,sTREM2 promotes microglial proliferation and migration.We also found that sTREM2 enhances microglial uptake and degradation of Aβ.Subsequent experimental results demonstrate that sTREM2 ameliorates the impaired synaptic plasticity in 5xFAD mice.Interestingly,depletion of microglia with a CSF1R inhibitor,PLX3397,abolishes the neuroprotective effects of sTREM2.Direct incubation of primary neurons with sTREM2 has no effect on mEPSCs,mIPSCs or the abundance of synaptic proteins.Taken together,this study reveals for the first time that sTREM2 ameliorates the pathological phenotypes of 5xFAD mice by regulating the functions of microglia,and provides the insights for the therapeutic strategies in the treatment for AD.