Microglia mediate neurocognitive deficits by eliminating C1q tagged synapses in sepsis-associated encephalopathy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA817210 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18356500.fastq.gz | Fastqsanger.gz | |||
| SRR18356501.fastq.gz | Fastqsanger.gz | |||
| SRR18356502.fastq.gz | Fastqsanger.gz | |||
| SRR18356503.fastq.gz | Fastqsanger.gz | |||
| SRR18356504.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-10-17 | GSE198871 | GEO
Project description:Sepsis-associated encephalopathy (SAE) is a severe and frequent complication of sepsis causing delirium, coma, and long-term cognitive dysfunction. We identified microglia and C1q complement activation in hippocampal autopsy tissue of patients with sepsis and increased C1q-mediated synaptic pruning in a murine polymicrobial sepsis model. Unbiased transcriptomics of hippocampal tissue and isolated microglia derived from septic mice revealed an involvement of the innate immune system, complement activation, and up-regulation of lysosomal pathways during SAE in parallel to neuronal and synaptic damage. Microglial engulfment of C1q-tagged synapses could be prevented by stereotactic intrahippocampal injection of a specific C1q-blocking antibody. Pharmacologically targeting microglia by PLX5622, a CSF1-R inhibitor, reduced C1q levels and the number of C1q-tagged synapses, protected from neuronal damage and synapse loss, and improved neurocognitive outcome. Thus, we identified complement-dependent synaptic pruning by microglia as a crucial pathomechanism for the development of neuronal defects during SAE.
| S-EPMC10219600 | biostudies-literature
Project description:Synapse loss and glial activation are hallmarks of Alzheimer's disease (AD). In Tau P301S transgenic mice, the complement pathway contributes to neuronal damage through microglial elimination of synapses. Here, we used unbiased proteomic profiling of postsynaptic density (PSD) fractions from Tau P301S mice in C1q-WT versus C1q knockout backgrounds to identify C1q-dependent changes at synapses. Integrative multi-omics analysis revealed that astrocyte- and microglia- specific proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. The same set of glial proteins (including C1q, C4, Gpnmb, and S100a4) is elevated in human AD synaptic fractions, and C4 levels are raised in cerebrospinal fluid (CSF) from AD patients. Besides microglia, we show that astrocytes contribute substantially to excitatory and inhibitory synapse engulfment in Tau P301S hippocampus. Based on staining of synapse markers within lysosomes, astrocytes showed preference for excitatory synapses whereas microglia preferred to engulf inhibitory synapse markers. Genetic deletion of C1q reduced astrocytic eating of excitatory and inhibitory synapses in Tau P301S mice, and rescued synapse density. Together, our data indicate that astrocytes contact and phagocytose synapses in a C1q- dependent manner and thereby contribute to synapse loss and neurodegeneration in AD.
2021-11-03 | MSV000088313 | MassIVE
Project description:We have data from a previous microarray experiment which shows that C1q elicits macrophages to express genes important for clearance of dead (apoptotic) cells. In this experiment we want to determine the signaling mechanism by which C1q is turning on macrophage gene expression. For our control (sample 1-3) we heated C1q to denature it so it is inactive. We also want to know which portion of C1q is responsible for activation the macrophage so we generated C1qtails (samples 4-5). We also have macrophages treated with the whole C1q molecule (7-9). And finally we have a cell line (J774) treated with C1q but does not activate the cells (samples 10-12). Bone marrow derived macrophages or J774 cells were adhered to heat inactivated C1q, C1q tails or C1q for 18 hours. Cells were harvested and RNA was isolated and converted to double stranded cDNA and subsequently labeled and hybridized onto NimbleGen mouse gene expression array [100718_MM9_EXP] using Nimblegen Hybridization system 4 according to manufacturerM-bM-^@M-^Ys instructions (Roche)
2014-07-10 | E-GEOD-48619 | biostudies-arrayexpress
Project description:We have data from a previous microarray experiment which shows that C1q elicits macrophages to express genes important for clearance of dead (apoptotic) cells. In this experiment we want to determine the signaling mechanism by which C1q is turning on macrophage gene expression. For our control (sample 1-3) we heated C1q to denature it so it is inactive. We also want to know which portion of C1q is responsible for activation the macrophage so we generated C1qtails (samples 4-5). We also have macrophages treated with the whole C1q molecule (7-9). And finally we have a cell line (J774) treated with C1q but does not activate the cells (samples 10-12).
2014-07-10 | GSE48619 | GEO
Project description:Sepsis is a severe global health issue with high mortality rates, and sepsis-associated encephalopathy (SAE) further exacerbates this risk. While recent studies have shown the migration of gut immune cells to the lungs after sepsis, their impact on the central nervous system remains unclear. Our research demonstrates that sepsis could induce the migration of IL-7Rhigh CD8low γδ T17 cells from the small intestine to the meninges, where they secrete IL-17A, impairing mitochondrial function in microglia and activating the cGAS-STING-C1q pathway. This process is accompanied by inhibited ubiquitination of STING at the K150 site, resulting in STING accumulation and increased release of C1q-tagged hippocampal synapses, which are subsequently pruned by activated microglia. Importantly, 4-Octyl itaconate mitigates the excessive synaptic pruning by inhibiting γδ T17 cell migration and promoting STING ubiquitination, thereby alleviating SAE. Our findings reveal a novel mechanism of synaptic pruning by microglia via the cGAS-STING-C1q pathway, emphasize the critical role of gut-derived γδ T17 cell migration to the meninges in SAE, and highlight the importance of STING ubiquitination in modulating C1q-mediated excessive synaptic pruning.
2024-10-28 | PXD057241 |
Project description:Longitudinal PET imaging of Alzheimer models reveals synaptic rescue by an mGluR5 modulator with selective normalization of neuronal transcriptomes. Alzheimer’s disease symptoms are initiated by synapse loss in the setting of microglial reactivity, but the basis for immune mediator attack on synapses is not clear. The mGluR5 silent allosteric modulator (SAM), BMS-984923, prevents Alzheimer’s triggered aberrant synaptic signaling while preserving physiological Glu activation. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB PET at doses 250-fold below adverse effect doses in rodent and non-human primate. For aged transgenic and double knock-in mouse Alzheimer’s models, SV2A PET imaging with [18F]SynVesT-1 reveals cortical and hippocampal synapse density decreases, which are fully recovered by SAM treatment. The disease-modifying benefit persists after drug washout. Tau accumulation in double knock-in mice is also reduced by SAM treatment. Single nuclei transcriptomics demonstrate that SAM treatment normalizes expression patterns to a much greater extent in neurons than glia. Production of the microglial mediator, C1q, is not altered by the mGluR5 compound, but Alzheimer gene-dependent C1q localization to synapses and synaptic engulfment are prevented. Thus, selective modulation of mGluR5 reverses neuronal gene expression changes to protect synapses from damage by microglial mediators.
2022-06-01 | GSE171095 | GEO
Project description:Pulmonary fibrosis (PF) is a progressive fibrotic disease with a poor prognosis and suboptimal therapeutic options. The complement molecule C1q, which plays an important role in the phagocytic capacity of macrophages, has recently been reported to exacerbate several fibrosis-related diseases. On the other hand, there are still no reports in PF. Here, we analyzed gene expression changes of C1q-administrated murine lungs.
2024-03-31 | GSE184445 | GEO
Project description:Pulmonary fibrosis (PF) is a progressive fibrotic disease with a poor prognosis and suboptimal therapeutic options. The complement molecule C1q, which plays an important role in the phagocytic capacity of macrophages, has recently been reported to exacerbate several fibrosis-related diseases. On the other hand, there are still no reports in PF. Here, we analyzed the effect of C1q treatment on lung fibroblasts.
2024-03-31 | GSE184438 | GEO
Project description:Identification of transcriptional profiles stimulated by the complement protein C1q in rat immature neurons associated with the C1q-dependent neuroprotection observed in vitro. Use of the unbiased whole genome microarray approach to identify genes regulated by C1q. Immature neurons grown in vitro for 3 days were stimulated with 10 nM C1q for 3h.
2011-03-07 | E-GEOD-18860 | biostudies-arrayexpress