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

Nature neuroscience 2022 Jan

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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. © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

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. TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nature neuroscience. 2022 Jan;25(1):26-38