Brain Genexpession of a mouse modle of Sepsis-associated encephalopathy (SAE)
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PROVIDER: PRJNA705148 | ENA |
REPOSITORIES: ENA
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Project description:Sepsis-associated encephalopathy (SAE) is a major and frequent complication in patients with sepsis resulting in delirium and premature death. Sepsis survivors commonly suffer from long-term cognitive impairment causing immense burden on patients, caregivers, and economic health systems. Underlying pathophysiology of SAE related cognitive deficits is largely unresolved, Thus treatment options are missing. We report that experimental polymicrobial sepsis in mice induces synaptic pathology in the central nervous system underlying defective long-term potentiation and cognitive dysfunction. Analysis of differentially expressed genes revealed severely affected downregulation of genes related to neuronal and synaptic signaling in the brain, e.g. of the activity-regulated cytoskeleton-associated protein (Arc ), of the transcription-regulatory EGR family, and of the dual-specificity phosphatase 6 (Dusp6). On the protein level, ARC expression and mitogen-activated protein (MAP) kinase signaling in the brain was disturbed during SAE. For targeted rescue of dysregulated synaptic signaling and plasticity, we overexpressed ARC in the hippocampus by bilateral in-vivo stereotactic microinjection of an adeno-associated virus containing a neuron-specific plasmid of the Arc transgene. Hereby, defective synaptic plasticity and signaling in the hippocampus were restored and memory function improved. Accordingly, synaptic plasticity, neuronal spine pathology, and memory dysfunction also improved when post-septic mice were subjected to enriched environment demonstrating the potential for activity-induced recovery of long-term cognitive dysfunction. Together, we identified synaptic pathology of neurocognitive dysfunction after severe systemic infection and provide a proof-of-concept approach to interfere with SAE pathomechanisms leading to cognitive improvement.
2021-02-27 | GSE167610 | GEO
Project description:Sepsis-associated encephalopathy (SAE) affects up to 70% ofSepsis-associated encephalopathy (SAE) affects up to 70% of patients in intensive care units with severe systemic infection. However, the exact pathological mechanisms behind SAE remain unclear. In this study, we aimed to investigate the protective effects of flavonoid components extracted from CCL seeds on SAE animals and evaluate the transcriptomic alterations in the hippocampus using RNA sequencing. Our results showed that CCL seed extract improved learning and memory abilities and structural integrity of the blood-brain barrier in CLP-induced SAE animal models. RNA sequencing revealed that CCL treatment reversed SAE-induced transcriptomic alterations in the hippocampus. Additionally, CCL significantly reduced inflammation (TNF-α， IL-2, and IL-6) and oxidative stress (MDA and SOD activity), as well as inhibited neuron apoptosis in brain tissues. Furthermore, CCL restored the PI3K/AKT signaling pathway, leading to Nrf2 nuclear translocation and HO-1 expression both in vitro and in vivo. The PI3K inhibitor LY294002 blocked CCL's anti-apoptotic, anti-inflammatory, and anti-oxidative effects, demonstrating that CCL's bioactivities are dependent on the PI3K/AKT signaling pathway. In conclusion, CCL exhibits significant neuroprotective properties and may be a promising candidate for further clinical trials in SAE treatment.
2024-06-08 | GSE249589 | GEO
Project description:Background: Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis. While several studies have reported the proteomic alteration in plasma, urine, heart, etc. of sepsis, few research focused on the brain tissue. This study aims at discovering the differentially abundant proteins in the brains of septic rats to identify biomarkers of SAE. Methods: The Prague-Dawley rats were randomly divided into sepsis (n = 6) or sham (n = 6) groups, and then the whole brain tissue was dissected at 24 h after surgery for further protein identification by TMT-LC–MS/MS-based proteomics. Ingenuity pathway analysis, Gene ontology knowledgebase, and STRING database are used to explore the biological significance of proteins with altered concentration. Results: Among the total of 3163 proteins identified in the brain tissue, 57 were increased while 38 were decreased in the sepsis group compared to the sham group. Bioinformatic analyses suggest that the differentially abundant proteins are highly related to cellular microtubule metabolism, energy production, nucleic acid metabolism, neurological disease, etc. Additionally, acute phase response signaling was possibly activated and PI3K/AKT signaling was suppressed during sepsis. An interaction network established by IPA revealed that Akt1, Gc-globulin, and ApoA1 were the core proteins. The increase of Gc-globulin and the decrease of Akt1 were confirmed by Western blot. Conclusions: Based on the multifunction of these proteins in several brain diseases, we first propose that Gc-globulin, ApoA1, PI3K/AKT pathway, and acute phase response proteins (hemopexin and cluster of alpha-2-macroglobulin) can potentially be diagnosis biomarkers, therapeutic targets, and prognosis indicators of SAE. These results may provide new insights into the pathologic mechanism of SAE, yet further research is required to explore the functional implications and clinical applications of the differentially abundant proteins in the brains of sepsis group.
2023-03-10 | PXD035112 | Pride
Project description:Molecular pathways mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. Here, we report that in mice during the first 6 hours of peripheral lipopolysaccharide (LPS)-evoked systemic inflammation (6 hpi), the plasma level of adenosine quickly increased and enhanced the tone of central extracellular adenosine which then provoked neuroinflammation by triggering early astrocyte reactivity. Specific ablation of astrocytic A1 adenosine receptors (A1ARs) prevented this early reactivity and reduced the levels of inflammatory factors (e.g., CCL2, CCL5, and CXCL1) in astrocytes, thereby alleviating microglial reaction, ameliorating blood-brain barrier disruption, peripheral immune cell infiltration, neuronal dysfunction, and depression-like behaviour in the mice. Chemogenetic stimulation of Gi signaling in A1AR-deficent astrocytes at 2 and 4 hpi of LPS injection could restore neuroinflammation and depression-like behaviour, highlighting astrocytes rather than microglia as early drivers of neuroinflammation. Our results identify early astrocyte reactivity towards peripheral and central levels of adenosine as a novel pathway driving SAE and highlight the potential of targeting A1ARs for therapeutic intervention.
2024-06-23 | GSE248275 | GEO
Project description:Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explore the influence of NAT10-mediated mRNA acetylation on SAE and the mechanisms underlying cognitive dysfunction in this context. SAE was induced in C57BL/6 J male mice through cecal ligation and puncture (CLP) surgery. In vivo, we observed a significant increase in NAT10 expression in the excitatory neurons of the hippocampal the dentate gyrus (DG) in CLP mice, and this change was accompanied by a trend toward an increase in mRNA acetylation. Specific knockout of Nat10 in neurons led to an improvement in cognitive dysfunction in septic mice. Proteomic analysis and RNA immunoprecipitation and real-time quantitative polymerase chain reaction (RIP-qPCR) revealed GABABR1 as a crucial downstream target of NAT10. Nat10 deletion reduced GABABR1 expression, subsequently weakening inhibitory postsynaptic currents in hippocampal DG neurons. Additionally, RNA sequencing (RNA-seq) revealed an increase in hippocampal inflammation post-CLP, characterized by the excessive activation of microglia and the release of inflammatory mediators. These factors were linked to the increased NAT10 expression in neurons. Treatment with PLX3397, a microglia depleting agent, resulted in a reduction in NAT10 and GABABR1 expression in neurons, which correlated with improvements in cognitive dysfunction induced by SAE. Taken together, our findings revealed that after CLP, NAT10 in neurons of the hippocampal DG region promotes GABABR1 expression by acetylating its mRNA, leading to cognitive dysfunction. These findings provide new insights into the molecular pathogenesis of SAE and suggest potential therapeutic targets for addressing cognitive deficits in septic patients.
2024-08-13 | GSE253309 | GEO
Project description:Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction caused by sepsis. Neuroinflammation induced by sepsis is considered a potential mechanism of SAE; however, very little is known about the role of the meningeal lymphatic system in SAE. The aged mice with SAE showed a significant decrease in the drainage of OVA-647 into the dCLNs and the coverage of the Lyve-1 in the meningeal lymphatic, indicating that sepsis impaired meningeal lymphatic drainage and morphology. The meningeal lymphatic function of aged mice was more vulnerable to sepsis in comparison to young mice. Sepsis also decreased the protein levels of caspase-3 and PSD95, which was accompanied by reductions in the activity of hippocampal neurons. Microglia were significantly activated in the hippocampus of SAE mice, which was accompanied by an increase in neuroinflammation, as indicated by increases in interleukin-1 beta, interleukin-6 and Iba1 expression. Cognitive function was impaired in aged mice with SAE. However, the injection of AAV1-VEGF-C significantly increased coverage in the lymphatic system and tracer dye uptake in dCLNs, suggesting that AAV1-VEGF-C promotes meningeal lymphangiogenesis and drainage. Furthermore, AAV1-VEGF-C reduced microglial activation and neuroinflammation and improved cognitive dysfunction. Improvement of meningeal lymphatics also reduced sepsis-induced expression of disease-associated genes in aged mice. Pre-existing lymphatic dysfunction by ligating bilateral dCLNs aggravated sepsis-induced neuroinflammation and cognitive impairment.
2023-11-30 | GSE247222 | GEO
Project description:Sepsis associated encephalopathy (SAE), a common complication of sepsis, seriously affect the prognosis and quality of life to sepsis patients. Microglia activation is vital to the neuroinflammation and the pathology of SAE. Mild hypothermia, that a useful procedure in the treatment of traumatic brain injuries, was found to suppress microglia activation. In present study, in vitro cultured BV-2 microglial cells stimulated with LPS was employed as the model of microglia activation. The altered signitures of lncRNAs, circRNAs and mRNAs of LPS exposure and mild hypothermia were arrayed by using the Agilent ceRNA Microarray Chip.
2021-11-10 | GSE171696 | GEO
Project description:Sepsis-associated encephalopathy (SAE) is associated with increased risk of long-term cognitive impairment. SAE is driven, at least in part, by brain endothelial dysfunction in response to systemic cytokine signaling. However, the mechanisms driving SAE and its consequences remain largely unknown. Here, we performed translating ribosome affinity purification and RNA-sequencing (TRAP-seq) from the brain endothelium to determine the transcriptional changes after an acute endotoxemic (LPS) challenge. LPS induced a strong acute transcriptional response in the brain endothelium that partially correlates with the whole brain transcriptional response and suggested an endothelial-specific hypoxia response. Consistent with a crucial role for IL-6, loss of the main regulator of this pathway, SOCS3, leads to a broadening of the population of genes responsive to LPS, suggesting that an overactivation of the IL-6/JAK/STAT3 pathway leads to an increased transcriptional response that could explain our prior findings of severe brain injury in these mice. To identify any potential sequelae of this acute response, we performed brain TRAP-seq following a battery of behavioral tests in mice after apparent recovery. We found that the transcriptional response returns to baseline within days post-challenge, but reductions in gene expression regulating protein translation and respiratory electron transport remained. We observed that mice that recovered from the endotoxemic shock showed mild, sex-dependent cognitive impairment, suggesting that the acute brain injury led to sustained effects. A better understanding of the transcriptional and non-transcriptional changes in response to shock is needed in order to prevent and/or revert the devastating consequences of septic shock.
2024-08-06 | GSE253438 | GEO
Project description:Microglia mediate neurocognitive deficits by eliminating C1q tagged synapses in sepsis-associated encephalopathy
| PRJNA817210 | ENA
Project description:Sepsis-associated encephalopathy is a common complication during systemic inflammation. Microglia are key player in this process. For a better understanding we compared isolated microglia from mice at day 3 and day 20 following induction of polymicrobial sepsis. We found a long-lasting inflammatory response of microglia following sepsis.
2022-10-17 | GSE198862 | GEO