TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration
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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.
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TREM2 mutations are risk factors for PD and ALS.
“TREM2 mutations were also reported to be risk factor for PD and ALS.245,246”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [246]
The Introduction (page unavailable) reports a study linking the TREM2 R47H variant to increased sporadic ALS risk, but says the ALS association remains debated because another study found none. Parkinson’s disease appears only in the title of a cited study in the References (page unavailable); this paper does not itself discuss PD risk. The claim therefore presents both associations more firmly than this source supports. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe link between the TREM2 mutant and the FTD-like manifestation may be partly explained by reduced TDP-43 clearance by microglia.
“This finding may partly explain the link between the TREM2 mutant and the FTD-like manifestation.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [347]
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References 91 · Cited by 157
Research works printed but not linked: 1
- [62]Leyns CEG, TREM2 function impedes tau seeding in neuritic plaques. Nat Neurosci (2019). PMC6660358 31235932
- Authors
- Xie, M., Liu, Y. U., Zhao, S., Zhang, L., Bosco, D. B., Pang, Y.-P., Zhong, J., Sheth, U., Martens, Y. A., Zhao, N., Liu, C.-C., Zhuang, Y., Wang, L., Dickson, D. W., Mattson, M. P., Bu, G., & Wu, L.-J.
- Affiliations
- Mayo Clinic (US)
- Mayo Clinic in Florida (US)
- Johns Hopkins University (US)
- Corresponding author
- Liu, Yong U.
- Wu, Long-Jun
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2021-12-16
- Volume
- 25
- Issue
- 1
- Pages
- 26-38
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC8741737
- OpenAlex
- W4226174907
- Cited by
- 157
- References
- 91
- Citations by year
- 2026: 25 · 2025: 46 · 2024: 43 · 2023: 26 · 2022: 16 · 2021: 1
- FWCI
- 9.01
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG066395, R21AG064159)
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS088627)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- TREM2, TDP-43, microglia, neuroprotection, amyotrophic lateral sclerosis, phagocytosis, protein-protein interaction, CD11c, microglial subpopulations, motor impairment, neurodegeneration
- MeSH terms
- Neuroprotection, Animals, DNA-Binding Proteins, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Microglia, Neurodegenerative Diseases, Mice
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