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

Abstract

Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, in the central nervous system, is exclusively expressed on microglia. TREM2 variants have been linked to increased risk for neurodegenerative diseases, but the functional effects of microglial TREM2 remain largely unknown. To this end, we investigated TAR-DNA binding protein 43 kDa (TDP-43)-related neurodegenerative disease via viral-mediated expression of human TDP-43 protein (hTDP-43) in neonatal and adult mice or inducible expression of hTDP43 with defective nuclear localization signals in transgenic mice. We found that TREM2 deficiency impaired microglia phagocytic clearance of pathological TDP-43, and enhanced neuronal damage and motor function impairments. Mass cytometry analysis revealed that hTDP-43 induced a TREM2-dependent subpopulation of microglia with high CD11c expression and higher 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, in hTDP-43-expressing transgenic mouse brains. We computationally identified the region within hTDP-43 that interacts with TREM2 and observed the potential interaction in ALS patient tissues. Our data reveal the novel interaction between TREM2 and TDP-43, highlighting that TDP-43 is a possible ligand for microglial TREM2 and the interaction mediates neuroprotection of microglial TREM2 in TDP-43-related neurodegeneration.

TREM2 mediates MHCII-associated CD4+T cell response against gliomas

“…The Trem2 -/line was kindly provided by Dr. Marco Colonna at the Washington University School of Medicine, St. Louis, and was bred at Mayo Clinic (Xie et al, 2022a). Wild type mouse line was purchased from Jackson Laboratory.…”

“…As a cell surface receptor, TREM2 is expressed exclusively in microglia (Colonna and Wang, 2016) in the central nervous system (CNS), macrophages (Do et al, 2022) and dendritic cells (DCs) (Bouchon et al, 2001) (Ulland and Colonna, 2018). The deficiency of TREM2 impairs the ability of microglia to sense and degrade numerous antigenic materials, including but not limited to pathogens (N'Diaye et al, 2009), apoptotic neurons (Takahashi et al, 2005), β-amyloid (Wang et al, 2015;Wang et al, 2016;Zhao et al, 2018), TAR DNA binding protein 43 (TDP-43) (Xie et al, 2022a), myelin (Cantoni et al, 2015), and neuronal synapses (Scott-Hewitt et al, 2020). Early studies reported that upon ligation of TREM2, genes related to MHC class II rapidly upregulate (Bouchon et al, 2001).…”