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

Na Zhao, Wenhui Qiao, Fuyao Li, Yingxue Ren, Jiaying Zheng, Yuka A. Martens, Xusheng Wang, Ling Li, Chia Chen Liu, Kai Chen, Yiyang Zhu, Tadafumi C. Ikezu, Zonghua Li, Axel D. Meneses, Yunjung Jin, Joshua A. Knight, Yixing Chen, Ligia Bastea, Cynthia Linares, Berkiye SonustunLucy Job, Madeleine L. Smith, Manling Xie, Yong U. Liu, Anthony D. Umpierre, Koichiro Haruwaka, Zachary S. Quicksall, Peter Storz, Yan W. Asmann, Long Jun Wu, Guojun Bu

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere20212479
JournalJournal of Experimental Medicine
Issue number12
StatePublished - Dec 5 2022

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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