Differential Effects of Partial and Complete Loss of TREM2 on Microglial Injury Response and Tauopathy [RNA-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA486277 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Late-onset Alzheimer’s disease is the most common form of dementia. A rare hemizygous variant in a microglial-expressed gene, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), significantly increases risk for late-onset Alzheimer’s disease. This variant is thought to cause loss of function, inducing TREM2 haploinsufficiency. The ramifications of TREM2 haploinsufficiency on microglial function and tau pathology are major gaps in the field. We find that in contrast to the protective effects of complete TREM2 deficiency, TREM2 haploinsufficiency exacerbates tau pathology, inflammation, and atrophy at a late stage of disease in a mouse model of tauopathy. The differential effects of partial and complete loss of TREM2 are important considerations for TREM2-targeted therapeutic strategies.
2018-09-20 | GSE118628 | GEO
Project description:Differential Effects of Partial and Complete Loss of TREM2 on Microglial Injury Response and Tauopathy
| PRJNA486276 | ENA
Project description:The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis at the single-nuclei level from brain tissue of AD patients with the R47H mutation or the common variant (CV)-TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously-identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with R47H mutation or CV, and found that R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Akt signaling, and elevation of a subset of disease-associated microglial signatures. Pharmacological Akt inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with tau fibrils. Strikingly, in R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster, and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a novel microglial modulating strategy to treat AD.
2021-12-06 | GSE140670 | GEO
Project description:The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis at the single-nuclei level from brain tissue of AD patients with the R47H mutation or the common variant (CV)-TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously-identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with R47H mutation or CV, and found that R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Akt signaling, and elevation of a subset of disease-associated microglial signatures. Pharmacological Akt inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with tau fibrils. Strikingly, in R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster, and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a novel microglial modulating strategy to treat AD.
2021-12-06 | GSE136389 | GEO
Project description: Not available
| S-EPMC6176614 | biostudies-literature
Project description:Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. The link between mutations in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a microglia-expressed gene, and the increased risk for developing late-onset AD suggests a detrimental role for microglia in disease pathophyioslogy. Hemizygous TREM2 mutations are posited to increase risk for AD through loss-of-function haploinsufficiency. The effects of TREM2 haploinsufficiency on tau pathology and tau-associated deficits have not yet been characterized. Using in vivo imaging, we showed that TREM2 haploinsufficiency, but not complete loss of TREM2, resulted in a striking agedependent impairment in microglia’s response to injury without affecting baseline motility. This TREM2-dependent effect on microglial motility is consistent with transcriptomic alterations in cell motility uncovered with unbiased RNAsequencing analysis. Moreover, TREM2 haploinsufficiency, but not complete loss of TREM2, exacerbated phosphorylated tau pathology in transgenic mice expressing mutant human tau. In addition, TREM2 haploinsufficiency increased tau inclusions and tau-mediated inflammation without further exacerbating neuronal loss. Our findings demonstrate for the first time that TREM2 haploinsufficiency induces deficits in a tauopathy mouse model, supporting the notion that the hemizygous missense variant results in loss-of-function.
2018-09-20 | GSE107293 | GEO
Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),
2015-07-06 | E-GEOD-70475 | biostudies-arrayexpress
Project description:Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to neurodegenerative disease risk. However, the function of TREM in neurodegeneration is still unclear. Here we investigated the role of microglial TREM2 in TAR-DNA binding protein 43 kDa (TDP-43)-related neurodegeneration using viral-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 hTDP-43 induced a TREM2-dependent subpopulation of microglia with high CD11c expression and 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 as well as in ALS patient tissues. We computationally identified the region within hTDP-43 that interacts with TREM2. Our data highlights that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection effects of microglia in TDP-43-related neurodegeneration.
2022-08-12 | PXD029429 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-09-20 | GSE118630 | GEO
Project description:The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and clinical dementia status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains. Further characterization of microglia revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously-identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils as well as rescued the tauopathy-induced synapse loss in R47H heterozygous mice. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.
2021-08-18 | GSE181903 | GEO