Zhong et al. describe two novel roles for soluble TREM2 (sTREM2) in regulation of proinflammatory responses and prevention of cellular apoptosis in microglia.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.

Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, hasrecently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis in Trem2 Ϫ / Ϫ mouse brains, induced cell cycle arrest at the G 1 /S checkpoint, and decreased the stability of ␤-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes, including cell survival. TREM2 stabilized ␤-catenin by inhibiting its degradation via the Akt/GSK3␤ signaling pathway. More importantly, treatment with Wnt3a, LiCl, or TDZD-8, which activates the ␤-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis in Trem2 Ϫ / Ϫ microglia and/or in Trem2 Ϫ / Ϫ mouse brain. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/␤-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.

BackgroundTREM2 is an innate immune receptor specifically expressed in microglia. Coding variations in TREM2 have been reported to increase the risk for Alzheimer’s disease (AD) and other neurodegenerative diseases. While multiple studies support a role for TREM2 in microglial recruitment to amyloid plaques, the chemoattractant factor modulating TREM2-dependent microglial responses has not been defined.MethodsPotential binding of oligomeric amyloid-β 1–42 (oAβ1–42) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oAβ1–42 to activate TREM2 signaling pathways was examined by analyzing the phosphorylation of Syk and Akt in primary microglia as well as TREM2-mediated signaling in a reporter cell system. Lastly, the functional outcome of oAβ1–42-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oAβ1–42-bearing brain areas in vivo.ResultsWe found that oAβ1–42 bound to TREM2 with high affinity and activated TREM2-dependent signaling pathway. Neither monomeric nor scrambled Aβ bound to TREM2 supporting a specific interaction between oAβ and TREM2. The disease-associated mutations of TREM2 reduced its binding affinity to oAβ1–42. Furthermore, we identified several positively charged amino acids within residues 31–91 of TREM2 that were crucial for its interaction with oAβ1–42. Importantly, oAβ1–42 promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner.ConclusionsOur data establish a critical link between oAβ1–42, a major pathological component of AD, and TREM2, a strong genetic risk factor for AD expressed in microglia, and suggest that such interaction contributes to the pathogenic events in AD by modulating microglial responses.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0247-7) contains supplementary material, which is available to authorized users.

Background: TREM2 is a DAP12-coupled receptor associated with neurodegenerative diseases. Results: Co-expression of DAP12 increased the level of TREM2 C-terminal fragment (TREM2-CTF) which suppressed the release of pro-inflammatory cytokines. Conclusion: A major function of DAP12 is to stabilize TREM2-CTF, which regulates inflammatory responses in microglia. Significance: Our studies unraveled a novel function of DAP12 and provided new link between TREM2/DAP12 complexes and neuroinflammation.