Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia

Using mouse models overexpressing human TREM2 in microglia, this study shows that WT TREM2 expression reduces amyloid deposition and suppresses disease-associated microglia only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer's disease (AD). As microglial responses modulated by TREM2 are central to AD pathogenesis, enhancing TREM2 signaling has been explored as an AD therapeutic strategy. However, the effective therapeutic window targeting TREM2 is unclear. Here, by using microglia-specific inducible mouse models overexpressing human wild-type TREM2 (TREM2-WT) or R47H risk variant (TREM2-R47H), we show that TREM2-WT expression reduces amyloid deposition and neuritic dystrophy only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. Single-cell RNA sequencing reveals suppressed disease-associated microglia (DAM) signature and reduced DAM population upon TREM2-WT expression in the early stage, whereas upregulated antigen presentation pathway is detected with TREM2-R47H expression in the middle stage. Together, our findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.

Automated summary

This study using mouse models demonstrates that overexpression of human TREM2 in microglia can reduce amyloid deposition and suppress disease-associated microglia in the early amyloid seeding stage, while the R47H variant exacerbates amyloid burden in the middle amyloid rapid growth stage. These findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.