TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration

Manling Xie, Yong U. Liu, Shunyi Zhao, Lingxin Zhang, Dale B. Bosco, Yuan Ping Pang, Jun Zhong, Udit Sheth, Yuka A. Martens, Na Zhao, Chia Chen Liu, Yongxian Zhuang, Liewei Wang, Dennis W. Dickson, Mark P. Mattson, Guojun Bu, Long Jun Wu

Research output: Contribution to journalArticlepeer-review


Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to risk of neurodegenerative disease. However, the function of TREM2 in neurodegeneration is still not fully understood. Here, we investigated the role of microglial TREM2 in TAR DNA-binding protein 43 (TDP-43)-related neurodegeneration using virus-mediated and transgenic mouse models. We found that TREM2 deficiency impaired phagocytic clearance of pathological TDP-43 by microglia and enhanced neuronal damage and motor impairments. Mass cytometry analysis revealed that human TDP-43 (hTDP-43) induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability. Using mass spectrometry (MS) and surface plasmon resonance (SPR) analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in human tissues from individuals with amyotrophic lateral sclerosis (ALS). We computationally identified regions within hTDP-43 that interact with TREM2. Our data highlight that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection of microglia in TDP-43-related neurodegeneration.

Original languageEnglish (US)
Pages (from-to)26-38
Number of pages13
JournalNature Neuroscience
Issue number1
StatePublished - Jan 2022

ASJC Scopus subject areas

  • General Neuroscience


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