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

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

doi:10.1038/s41593-021-00975-6

Abstract

Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to neurodegenerative disease risk. 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 kDa (TDP-43)-related neurodegeneration using viral-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 hTDP-43 induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability. Using mass spectrometry and surface plasmon resonance analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in ALS patient tissues. We computationally identified regions within hTDP-43 that interact with TREM2. Our data highlights that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection of microglia in TDP-43-related neurodegeneration.

Highlights

Microglia account for 5-10% of glial cells and serve as the principal immune cells of the central nervous system (CNS)
These findings indicate that neonatal ICV injection of human TDP-43 protein (hTDP-43) virus can induce typical TDP43 pathology and motor deficits in WT mice
Our results suggest that Triggering receptor expressed on myeloid cell 2 (TREM2) deficiency abolishes the hTDP-43-induced CD11c+ subpopulation of microglia, which plays a critical role in phagocytosing hTDP-43

Summary

Introduction

Microglia account for 5-10% of glial cells and serve as the principal immune cells of the central nervous system (CNS). TAR-DNA binding protein 43 kDa (TDP-43) was first identified in 1995 as a DNA binding protein and plays a critical role in regulating gene expression 7. It is the main component of the insoluble and ubiquitinated protein aggregates found in most ALS patients 8. Spatial gene expression analysis in both ALS mouse model and sporadic ALS patients implicates TREM2-mediated mechanism in disease pathogenesis [12,13]. We further demonstrated that microglial TREM2 interacts with pathological hTDP-43, suggesting a potential molecular mechanism underlying the neuroprotective function for microglia in TDP-43-mediated neurodegeneration

Results

DISCUSSION

Methods