Microglial Trem2 shapes neuronal bioenergetics during development
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ABSTRACT:
PROVIDER: PRJNA1047066 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27003652_1.fastq.gz | Fastqsanger.gz | |||
| SRR27003652_2.fastq.gz | Fastqsanger.gz | |||
| SRR27003653_1.fastq.gz | Fastqsanger.gz | |||
| SRR27003653_2.fastq.gz | Fastqsanger.gz | |||
| SRR27003654_1.fastq.gz | Fastqsanger.gz |
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Project description:Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in microglia, whose variants are associated with multiple neurodegenerative diseases. TREM2 receptor modulates phagocytosis, cytokine production and metabolism, enabling appropriate surveillance of the brain by microglia and ensuring their proper response to damage signals. Here, we demonstrate that TREM2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in hippocampal CA1 -but not in CA3- subfield display compromised energetic metabolism and defective basal, maximal and ATP-dependent respiration, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This is paralleled by a significant transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation and mitochondrial signatures. The developmental trajectories of the excitatory lineages indicate that lack of Trem2 causes a delay in the maturation of CA1 neurons, paired with specific alterations in the mitochondrial TOM complex which persist in the mature hippocampus. In addition, the mitochondrial defects and faulty neuronal differentiation are maintained also after neuron isolation from the brain context, suggesting that the lack of TREM2-mediated communication between microglia and neurons at early developmental windows is sufficient to derange the forthcoming maturation of neuronal metabolism. Our results unveil a novel role of TREM2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.
2024-01-15 | GSE249036 | GEO
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: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:TREM2 is a microglial-specific gene implicated in late-onset Alzheimer's Disease (AD). Recent studies have identified that Trem2-deficient mice exhibit transcriptional changes in microglial gene expression that minimize the upregulation of lipid metabolism and lysosomal genes in AD disease models. We detect similiarly attenuated expression of lipid metabolism genes in microglia isolated from brains of aged Trem2 knockout mice.
2019-12-21 | GSE134031 | GEO
Project description:We use genetically engineered human iPSC-derived microglia-like cells (iMG) to show that TREM2 signals through PLCγ2 to mediate cell survival, phagocytosis, and lipid metabolism following myelin challenge. Loss of TREM2 or PLCγ2 signaling leads to a shared signature of transcriptional dysregulation that underlies these phenotypes. However, PLCγ2 also signals downstream of Toll-like receptors to mediate inflammatory responses in a TREM2-independent manner. Therefore, PLCγ2 activity regulates divergent microglial functions via distinct TREM2-dependent and -independent signaling and may be involved in the transition to a microglial state associated with neurodegenerative disease.
2020-05-24 | GSE144120 | GEO
Project description:TREM2 is a microglial-specific gene implicated in late-onset Alzheimer's Disease (AD). Recent studies have identified that Trem2-deficient mice exhibit transcriptional changes in microglial gene expression that minimize the upregulation of lipid metabolism and lysosomal genes in AD disease models. We find that chronic phagocytic challenge from demyelination generates similiarly attenuated expression of lysosomal and lipid metabolism genes in microglia isolated from Trem2 knockout mouse brain.
2019-12-21 | GSE124266 | GEO
Project description:TREM2 is a microglial-specific gene implicated in late-onset Alzheimer's Disease (AD). Recent studies have identified that Trem2-deficient mice exhibit transcriptional changes in microglial gene expression that minimize the upregulation of lipid metabolism and lysosomal genes in AD disease models. We find that chronic phagocytic challenge from demyelination generates similiarly attenuated expression of lysosomal and lipid metabolism genes in microglia isolated from Trem2 knockout mouse brain.
2019-12-21 | GSE130626 | GEO
Project description:CD33-/- and/or TREM2-/- mice were crossed with the 5xFAD mouse model of Alzheimer’s disease to generate single and double CD33/TREM2 knock-out mice on 5xFAD background. Transcriptome and gene expression analyses were performed to analyze the impact of CD33 and/or TREM2 knock-out on the transcriptome of microglia in the context of amyloid pathology. The results revealed that CD33 and/or TREM2 knock-out reprogrammed microglial gene expression signatures in 5xFAD mice in an age-dependent manner. Differential gene expression in 5xFAD;CD33-/- microglia depended on the presence of TREM2. These data suggest that TREM2 acts downstream of CD33.
2019-06-11 | GSE132508 | GEO
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: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