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TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration
Manling Xie1,2, Yong U Liu3,4, Shunyi Zhao1
1Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Abstract:
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.
Insights
Microglial TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is crucial for clearing toxic TDP-43 in neurodegeneration. Its absence worsens neuronal damage and motor deficits, highlighting TREM2
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Triggering receptor expressed on myeloid cell 2 (TREM2) is implicated in neurodegenerative disease risk.
- The precise function of TREM2 in neurodegeneration remains incompletely understood.
- TAR DNA-binding protein 43 (TDP-43) pathology is a hallmark of several neurodegenerative conditions.
Purpose of the Study:
- To investigate the role of microglial TREM2 in TDP-43-related neurodegeneration.
- To elucidate the interaction between TDP-43 and TREM2.
- To determine if TREM2-TDP-43 interaction mediates microglial neuroprotection.
Main Methods:
- Utilized virus-mediated and transgenic mouse models for TDP-43-related neurodegeneration.
- Employed mass cytometry to analyze microglial subpopulations.
- Applied mass spectrometry (MS) and surface plasmon resonance (SPR) for interaction analysis.
- Performed computational analysis to identify interacting regions.
Main Results:
- TREM2 deficiency impaired microglial phagocytic clearance of pathological TDP-43.
- TREM2 deficiency exacerbated neuronal damage and motor impairments.
- Human TDP-43 induced a TREM2-dependent microglial subpopulation with enhanced phagocytic capacity.
- Demonstrated direct interaction between TDP-43 and TREM2 in vitro, in vivo, and in human ALS tissues.
Conclusions:
- TDP-43 acts as a potential ligand for microglial TREM2.
- The TREM2-TDP-43 interaction is critical for microglial-mediated neuroprotection in TDP-43 proteinopathies.
- Targeting the TREM2-TDP-43 pathway may offer therapeutic strategies for neurodegenerative diseases.
