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

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

doi:10.1038/s41593-021-00975-6

Cited by 81 publications

(81 citation statements)

References 82 publications

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“…Increasing sTREM2 in the CNS has been reported to trigger microglia activation, promote microglia survival, and ameliorate pathological phenotypes (Zhong et al, 2017(Zhong et al, , 2019. Our studies revealed a potential role of sTREM2 in TDP-43 clearance in ALS (Xie et al, 2022). In addition, sTREM2 has been reported to be present on neuronal soma in both cortex and hippocampus of AD mice (Song et al, 2018), suggesting a potential role in removing apoptotic neuronal cells.…”

Section: Future Directionsmentioning

confidence: 50%

“…Our findings revealed a protective function of microglial TREM2 during ALS progression (Xie et al, 2022), thus increasing microglial TREM2 activity or expression at certain disease stages may alleviate ALS-related dysfunctions. To achieve this, pharmacological intervention or gene therapies, such as antisense oligonucleotides (ASOs), could be applied.…”

Section: Targeting Trem2 To Treat Alsmentioning

confidence: 64%

“…Phosphorylated DAP12 can recruit spleen tyrosine kinase (SYK) to activate its downstream signaling molecules, including phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase (ERK), and phospholipase Cγ (PLCγ) (Konishi & Kiyama, 2018;Zhou et al, 2018). We additionally found that TDP-43 can directly bind to extracellular domain of TREM2 in silico and by in vitro surface plasmon resonance assay, suggesting that TDP-43 is another potential ligand for TREM2 (Xie et al, 2022). Consistently, structural analysis showed that neurodegenerative disease related TREM2 mutations will impair TREM2 interacts with its ligand (Kober et al, 2016).…”

Section: Trem2 In Alsmentioning

confidence: 90%

“…Thus, microglial TREM2 could sense degenerating neurons and myelin debris in ALS. Recently, using ALS mouse models of TDP-43 proteinopathy, we demonstrated that TREM2 deficient microglia lost their phagocytic ability for TDP-43 inclusions, suggesting a protective role of TREM2 in TDP-43 induced neurodegeneration (Xie et al, 2022). To explore the potential mechanisms, we found that TREM2 interacts with TDP-43 in vitro and in vivo (Xie et al, 2022).…”

Section: Trem2 In Alsmentioning

confidence: 99%

“…Recently, using ALS mouse models of TDP-43 proteinopathy, we demonstrated that TREM2 deficient microglia lost their phagocytic ability for TDP-43 inclusions, suggesting a protective role of TREM2 in TDP-43 induced neurodegeneration (Xie et al, 2022). To explore the potential mechanisms, we found that TREM2 interacts with TDP-43 in vitro and in vivo (Xie et al, 2022). The exact mechanisms underlying TREM2 mediated recognition and phagocytosis of its substrates are unclear.…”

Section: Trem2 In Alsmentioning

confidence: 99%

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Microglial TREM2 in amyotrophic lateral sclerosis

Xie

Zhao

Bosco

et al. 2021

Developmental Neurobiology

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Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an aggressive motor neuron degenerative disease characterized by selective loss of both upper and lower motor neurons. The mechanisms underlying disease initiation and progression are poorly understood. The involvement of nonmotor neuraxis emphasizes the contribution of glial cells in disease progress. Microglia comprise a unique subset of glial cells and are the principal immune cells in the central nervous system (CNS). Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, within the CNS, is exclusively expressed on microglia and plays crucial roles in microglial proliferation, migration, activation, metabolism, and phagocytosis. Genetic evidence has linked TREM2 to neurodegenerative diseases including ALS, but its function in ALS pathogenesis is largely unknown. In this review, we summarize how microglial activation, with a specific focus on TREM2 function, affects ALS progression clinically and experimentally. Understanding microglial TREM2 function will help pinpoint the molecular target for ALS treatment.

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Section: Future Directionsmentioning

confidence: 50%

Section: Targeting Trem2 To Treat Alsmentioning

confidence: 64%

Section: Trem2 In Alsmentioning

confidence: 90%

Section: Trem2 In Alsmentioning

confidence: 99%

Section: Trem2 In Alsmentioning

confidence: 99%

See 3 more Smart Citations

Microglial TREM2 in amyotrophic lateral sclerosis

Xie

Zhao

Bosco

et al. 2021

Developmental Neurobiology

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Association between hippocampal microglia, AD and LATE‐NC, and cognitive decline in older adults

Kapasi,

Yu,

Leurgans

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONThis study investigates the relationship between microglia inflammation in the hippocampus, brain pathologies, and cognitive decline.METHODSParticipants underwent annual clinical evaluations and agreed to brain donation. Neuropathologic evaluations quantified microglial burden in the hippocampus, amyloid beta (Aβ), tau tangles, and limbic age‐related transactive response DNA‐binding protein 43 (TDP‐43) encephalopathy neuropathologic changes (LATE‐NC), and other common brain pathologies. Mixed‐effect and linear regression models examined the association of microglia with a decline in global and domain‐specific cognitive measures, and separately with brain pathologies. Path analyses estimated direct and indirect effects of microglia on global cognition.RESULTHippocampal microglia were associated with a faster decline in global cognition, specifically in episodic memory, semantic memory, and perceptual speed. Tau tangles and LATE‐NC were independently associated with microglia. Other pathologies, including Aβ, were not related. Regional hippocampal burden of tau tangles and TDP‐43 accounted for half of the association of microglia with cognitive decline.DISCUSSIONMicroglia inflammation in the hippocampus contributes to cognitive decline. Tau tangles and LATE‐NC partially mediate this association.

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APOE2 Exacerbates TDP‐43 Related Toxicity in the Absence of Alzheimer Pathology

Meneses

Koga

et al. 2023

Annals of Neurology

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Objective Recent evidence supports a link between increased TDP‐43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP‐43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP‐43 pathology and related neurodegeneration in the absence of typical AD pathologies. Methods We overexpressed human TDP‐43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe‐knockout (Apoe‐KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP‐43 overexpression‐related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP‐43 pathology in 160 postmortem brains from autopsy‐confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD‐MND) in the Mayo Clinic Brain Bank. Results We found that TDP‐43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe‐KO mice. In the motor cortex of the ALS and FTLD‐MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP‐43‐positive dystrophic neurites. Interpretation Our data suggest a genotype‐specific effect of APOE on TDP‐43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830–843

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

Cited by 81 publications

References 82 publications

Microglial TREM2 in amyotrophic lateral sclerosis

Microglial TREM2 in amyotrophic lateral sclerosis

Association between hippocampal microglia, AD and LATE‐NC, and cognitive decline in older adults

APOE2 Exacerbates TDP‐43 Related Toxicity in the Absence of Alzheimer Pathology

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