Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice

ABSTRACT: TPL2 (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates cytokine levels and activation states of microglia. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNAseq analysis indicates protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity promotes multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE196401 | GEO | 2023/08/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice

Project description:TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice

| PRJNA804717 | ENA

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα deletion in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deficient enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

2023-08-09 | PXD043877 | Pride

Polarized microtubule remodeling transforms activated microglia morphology and drives cytokine release

Project description:Microglial activation is a pathological hallmark in many neurodegenerative diseases. During activation, microglia undergo complex morphological changes, including loss of their characteristic ramified cell morphology, which is routinely used to detect and quantify inflammation in the brain. However, the molecular mechanisms enabling this morphological change and the relation between microglial cell morphology and its pathophysiological function are not understood. Here, proteomic profiling of activated microglia identified microtubule remodeling pathways as an early factor that drives the morphological change and subsequently controls cytokine responses. We found that activated microglia increase their microtubule dynamics to form a stable and centrosomally anchored microtubule array to facilitate efficient cytokine trafficking and release. Moreover, we identified cyclin-dependent kinase 1 (Cdk-1) as a critical upstream regulator of microtubule remodeling and morphological change in vitro and in vivo. These results demonstrate a critical role for microtubule dynamics and reorganization in microglial activation and modulating cytokine-mediated inflammatory responses.

| MSV000090254 | MassIVE

Polarized microtubule remodeling transforms the morphology of reactive microglia cells and drives cytokine release

Project description:Microglial reactivity is a pathological hallmark in many neurodegenerative diseases. During stimulation, microglia undergo complex morphological changes, including loss of their characteristic ramified morphology, which is routinely used to detect and quantify inflammation in the brain. However, the underlying molecular mechanisms and the relation between microglial morphology and their pathophysiological function are unknown. Here, proteomic profiling of lipopolysaccharide (LPS)-reactive microglia identified microtubule remodeling pathways as an early factor that drives the morphological change and subsequently controls cytokine responses. We found that LPS-reactive microglia reorganize their microtubules to form a stable and centrosomally anchored array to facilitate efficient cytokine trafficking and release. We identified cyclin-dependent kinase 1 (Cdk-1) as a critical upstream regulator of microtubule remodeling and morphological change in-vitro and in-situ. Cdk-1 inhibition also rescued tau and amyloid fibril-induced microglia changes. These results demonstrate a critical role for microtubule dynamics and reorganization in microglial reactivity and modulating cytokine-mediated inflammatory responses.

2023-09-21 | GSE238210 | GEO

Assessing the role of TPL2 in TauP301S mice

Project description:ScRNAseq analysis shows •TPL2 KD (kinase dead) reduced TauP301S dependent IEG and MHCII activation states in microglia •TPL2 KD reduced peripheral immune cell infiltration in TauP301S mouse brain

2022-07-16 | GSE180041 | GEO

Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease

Project description:Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n=11) and control brain (n=14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

2023-07-09 | GSE236268 | GEO

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα on tau pathology are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolic processes, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

2023-07-12 | GSE236875 | GEO

Genome-wide analysis of LPS-responsive gene expression by microglia cells in Ntg and LRRK2KO mouse brain

Project description:Analysis of LRRK2-regulation of microglia responce to the LPS at gene expression level. The hypothesis tested in the present study was whether LRRK2 influence the microglial phagocytosis- and neuroinflammation- related gene expression at mRNA level. Total RNA obtained from microglia cells isolated from Ntg or LRRK2KO mouse brain subjected to 6 or 24 hours of LPS treatment in vitro

2016-06-22 | E-GEOD-83562 | biostudies-arrayexpress

AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation

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

AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation

2021-12-06 | GSE136389 | GEO