Enhancing TREM2 expression activates microglia and modestly mitigates Tau pathology and neurodegeneration

TREM2, a microglia-specific receptor, is strongly associated with Alzheimer’s disease (AD) risk and modulates microglial responses critical to AD pathogenesis. However, its role in tauopathy and neurodegeneration remains unclear. Here, by using a PS19 tauopathy mouse model with inducible overexpression of human wild-type TREM2 (TREM2-WT) or the R47H variant (TREM2-R47H), we show that TREM2-WT overexpression modestly reduces soluble phosphorylated tau (p-tau) levels and mildly preserves neuronal integrity, whereas TREM2-R47H fails to impact p-tau levels or neurodegeneration. Single-cell RNA sequencing revealed that TREM2-WT enhances disease-associated microglia (DAM) signatures, while TREM2-R47H drives the MHCII+ microglial phenotypes. These findings demonstrate that TREM2-WT confers modest benefits in tauopathy models, whereas TREM2-R47H exhibits reduced functionality. Our study underscores the therapeutic potential of enhancing TREM2 activity to modulate microglial responses and mitigate neurodegeneration in AD.