AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation
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ABSTRACT:
PROVIDER: PRJNA753007 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15372700.fastq.gz | Fastqsanger.gz | |||
| SRR15372701.fastq.gz | Fastqsanger.gz | |||
| SRR15372702.fastq.gz | Fastqsanger.gz | |||
| SRR15372703.fastq.gz | Fastqsanger.gz | |||
| SRR15372704.fastq.gz | Fastqsanger.gz |
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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.
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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.
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Project description:We identified enrichment of a disease-enhancing, proinflammatory subpopulation of microglia in human AD patient brains with the R47H-TREM2 mutation, and uncovered that enhanced Akt signaling in microglia underlies the proinflammatory cytokine state and synaptic toxicity in our R47H-TREM2 tauopathy mouse model.
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Project description:We identified enrichment of a disease-enhancing, proinflammatory subpopulation of microglia in human AD patient brains with the R47H-TREM2 mutation, and uncovered that enhanced Akt signaling in microglia underlies the proinflammatory cytokine state and synaptic toxicity in our R47H-TREM2 tauopathy mouse model.
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Project description:AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation
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Project description:AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation
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Project description:AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states in via Akt hyperactivation
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Project description:The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). To understand its pathogenicity, we performed single-nuclei RNA-sequencing of cortical tissue from AD patients with R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status. we found that the R47H mutation is associated with cell type- and sex-specific transcriptional changes in human AD, with microglia exhibiting the most robust alterations. R47H-associated microglial subpopulations were characterized by hyperactivation of AKT, one of the signaling pathways downstream of TREM2, and enhanced inflammatory signatures. In tauopathy mouse models that carry one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, the mutation induced spatial memory deficits and exacerbated tau-mediated deficits in female mice. Similar to the human data, the disease-enhancing effects of R47H microglia were associated with robust increases in proinflammatory cytokines, Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures identified using single-cell sequencing from isolated microglia. Pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures in R47H microglia treated with tau fibrils. 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 brain immune responses to treat AD.
2022-07-16 | GSE154578 | GEO
Project description:Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer’s disease (AD). A number of mutations in the microglial protein TREM2 (triggering receptor expressed on myeloid cells 2) have been associated with increased risk for developing Alzheimer’s disease (AD), most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human iPSC-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a pro-inflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyper-responsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuron-microglia co-cultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism. These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.
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