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

Xie M, Liu YU, Zhao S, Zhang L, Bosco DB, Pang YP, Zhong J, Sheth U, Martens YA, Zhao N, Liu CC, Zhuang Y, Wang L, Dickson DW, Mattson MP, Bu G, Wu LJ

Nature neuroscience 2022

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.

17 Figures Extracted

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Characterizations of GFP-hTDP-43 expression in a neonatal TDP-43 mouse model. GFP-hTDP-43 expression was induced via intracerebroventricular injection...

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Characterizations of motor deficits and neuronal loss in a neonatal TDP-43 mouse model. GFP-hTDP-43 expression was induced via intracerebroventricular...

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TREM2 deficiency leads to increased accumulation of hTDP-43 protein. hTDP-43 protein expression was induced via intracerebroventricular injection of A...

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Phenotypic diversity of microglia in response to TDP-43 pathology by CyTOF. a , A representative gating strategy illustrating brain myeloid cell being...

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TREM2 deficiency attenuates hTDP-43-induced microglial activation. hTDP-43 protein expression was induced via intracerebroventricular injection of AAV...

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Characterizations of hTDP-43 expression mouse model via local virus injection in the primary motor cortex of adult mice. GFP-hTDP-43 or hTDP-43 was ex...

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TREM2 deficiency facilitates hTDP-43-induced neurodegeneration. GFP-hTDP-43 or hTDP-43 was expressed in the primary motor cortex of 2-month-old mice v...

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TDP-43 can be released from neurons and interact with TREM2 in vitro . a , Representative images of human iPSC derived neurons infected with AAV9.CAG...

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Human TREM2 interacting proteins in HEK293T cells. a , A schematic illustration of the SILAC methodology to identify human TREM2 interacting proteins ...

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hTDP-43 interacts with TREM2 in vivo in mouse brain. GFP-hTDP-43 was expressed in the primary motor cortex of 2-month-old mice via stereotactic intr...

Fig 1.

TREM2 deficiency aggravates hTDP-43-induced behavioral deficits and neurodegeneration. GFP tagged hTDP-43 protein (GFP-hTDP-43) expression was induced...

Fig 2.

TREM2 deficiency abolishes hTDP-43-induced CD11c + microglia subpopulation. hTDP-43 protein expression was induced via intracerebroventricular inject...

Fig 3.

TREM2 deficiency locks microglia into a homeostatic state in TDP-43-induced neurodegeneration. In adult local injection model, hTDP-43 or GFP-hTDP-43 ...

Fig 4.

TREM2 deficiency impairs microglial phagocytosis of pathological hTDP-43 protein. hTDP-43 or GFP-hTDP-43 was expressed in the primary motor cortex of ...

Fig 5.

TREM2 deficiency leads to increased accumulation of pathological hTDP-43 protein. GFP-hTDP-43 was expressed in the primary motor cortex of 2-month-old...

Fig 6.

hTDP-43 interacts with TREM2 in vitro and in vivo in mouse brain. a , hTDP-43 was co-immunoprecipitated with myc-hTREM2 in HEK 293T cells overexpr...

Fig 7.

hTDP-43 interacts with TREM2 in human tissues and in silico . a , TREM2 immunoblots of frozen autopsied cortex and spinal cord specimens of ALS patie...