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

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

来源：Nature Neuroscience, 2022, 25(1): 26-+.

DOI：10.1038/s41593-021-00975-6

• FRONTOTEMPORAL LOBAR DEGENERATION
• PROLIFERATION
• CELLS
• BETA
• RESPONSES
• RECOVERY
• SURVIVAL
• PROTEIN
• BINDS

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. @@@ Using mouse models of TDP-43 neurodegeneration, this study demonstrates that microglial TREM2 binds TDP-43 and thus mediates its phagocytic clearance. TDP-43 may serve as a possible ligand for microglial TREM2 in TDP-43-related neurodegeneration.