Gray but not white matter astroglia-specific connexin 43 ablation ameliorates neuroinflammation [Agilent]
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PROVIDER: PRJNA626564 | ENA |
REPOSITORIES: ENA
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Project description:Gray but not white matter astroglia-specific connexin 43 ablation ameliorates neuroinflammation
| PRJNA626575 | ENA
Project description:Gray but not white matter astroglia-specific connexin 43 ablation ameliorates neuroinflammation [Affymetrix]
| PRJNA626581 | ENA
Project description:Objective: We previously reported that white matter connexin43 (Cx43) may related to the severity of the multiple sclerosis (MS), whereas the role of gray matter Cx43 in demyelinating disease is unknown. It was considered MS lesions were only exist in white matter, but recent studies revealed that demyelinating lesions are also exist in the cerebral cortex. This fact suggest the possibility that gray matter is somewhat related to the pathophysiology of MS. In this study, we aimed to clarify the role of gray matter Cx43 in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Methods: We developed Cx43F/F;Glutamate aspartate transporter (GLAST)-CreER(T2)KI/+ mice as gray matter specific Cx43 conditional knock-out (Cx43cKO) mice. We induced MOG-EAE 10 days after tamoxifen injection, and analyze its clinical course and pathology. We used Cx43F/F mice as controls. Results: EAE was significantly milder in gray matter astrocyte-specific Cx43cKO mice from acute phase to chronic phase, as compared with control mice. Pathology demonstrated less demyelinating lesions and infiltrating cells. Infiltrating immune cells did not express Cx43 in the active demyelinating lesions of the lumbar cord in both groups. The expression level of Cx43 was similar between these two groups in the spleen and the inguinal lymph nodes. Interpretation: Acute KO of gray matter specific Cx43 before induction of EAE reduce its aggressiveness. This finding may suggest the possibility that gray matter Cx43 modify the MS pathophysiology.
2021-04-20 | GSE148929 | GEO
Project description:Objective: We previously reported that white matter connexin43 (Cx43) may related to the severity of the multiple sclerosis (MS), whereas the role of gray matter Cx43 in demyelinating disease is unknown. It was considered MS lesions were only exist in white matter, but recent studies revealed that demyelinating lesions are also exist in the cerebral cortex. This fact suggest the possibility that gray matter is somewhat related to the pathophysiology of MS. In this study, we aimed to clarify the role of gray matter Cx43 in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Methods: We developed Cx43F/F;Glutamate aspartate transporter (GLAST)-CreER(T2)KI/+ mice as gray matter specific Cx43 conditional knock-out (Cx43cKO) mice. We induced MOG-EAE 10 days after tamoxifen injection, and analyze its clinical course and pathology. We used Cx43F/F mice as controls. Results: EAE was significantly milder in gray matter astrocyte-specific Cx43cKO mice from acute phase to chronic phase, as compared with control mice. Pathology demonstrated less demyelinating lesions and infiltrating cells. Infiltrating immune cells did not express Cx43 in the active demyelinating lesions of the lumbar cord in both groups. The expression level of Cx43 was similar between these two groups in the spleen and the inguinal lymph nodes. Interpretation: Acute KO of gray matter specific Cx43 before induction of EAE reduce its aggressiveness. This finding may suggest the possibility that gray matter Cx43 modify the MS pathophysiology.
2021-04-20 | GSE148931 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-04-20 | GSE148932 | GEO
Project description:BackgroundBrain astroglia are activated preceding the onset of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We characterized the effects of brain astroglia on spinal cord inflammation, focusing on astroglial connexin (Cx)43, because we recently reported that Cx43 has a critical role in regulating neuroinflammation.MethodsBecause glutamate aspartate transporter (GLAST)+ astroglia are enriched in the brain gray matter, we generated Cx43fl/fl;GLAST-CreERT2/+ mice that were brain gray matter astroglia-specific Cx43 conditional knockouts (Cx43 icKO). EAE was induced by immunization with myelin oligodendroglia glycoprotein (MOG) 35-55 peptide 10 days after tamoxifen injection. Cx43fl/fl mice were used as controls.ResultsAcute and chronic EAE signs were significantly milder in Cx43 icKO mice than in controls whereas splenocyte MOG-specific responses were unaltered. Histologically, Cx43 icKO mice showed significantly less demyelination and fewer CD45+ infiltrating immunocytes, including F4/80+ macrophages, and Iba1+ microglia in the spinal cord than controls. Microarray analysis of the whole cerebellum revealed marked upregulation of anti-inflammatory A2-specific astroglia gene sets in the pre-immunized phase and decreased proinflammatory A1-specific and pan-reactive astroglial gene expression in the onset phase in Cx43 icKO mice compared with controls. Astroglia expressing C3, a representative A1 marker, were significantly decreased in the cerebrum, cerebellum, and spinal cord of Cx43 icKO mice compared with controls in the peak phase. Isolated Cx43 icKO spinal microglia showed more anti-inflammatory and less proinflammatory gene expression than control microglia in the pre-immunized phase. In particular, microglial expression of Ccl2, Ccl5, Ccl7, and Ccl8 in the pre-immunized phase and of Cxcl9 at the peak phase was lower in Cx43 icKO than in controls. Spinal microglia circularity was significantly lower in Cx43 icKO than in controls in the peak phase. Significantly lower interleukin (IL)-6, interferon-γ, and IL-10 levels were present in cerebrospinal fluid from Cx43 icKO mice in the onset phase compared with controls.ConclusionsThe ablation of Cx43 in brain gray matter astroglia attenuates EAE by promoting astroglia toward an anti-inflammatory phenotype and suppressing proinflammatory activation of spinal microglia partly through depressed cerebrospinal fluid proinflammatory cytokine/chemokine levels. Brain astroglial Cx43 might be a novel therapeutic target for MS.
| S-EPMC8180177 | biostudies-literature
Project description:Astroglia are integral to brain development and the emergence of neurodevelopmental disorders. However, studying the pathophysiology of human astroglia using brain organoid models has been hindered by inefficient astrogliogenesis. In this study, we introduce a robust method for generating astroglia-enriched organoids through BMP4 treatment during the neural differentiation phase of organoid development. Our RNA sequencing analysis reveals that astroglia developed within these organoids exhibit advanced developmental characteristics and enhanced synaptic functions compared to those grown under traditional two-dimensional conditions, particularly highlighted by increased neurexin (NRXN)-neuroligin (NLGN) signaling. Cell adhesion molecules, such as NRXN and NLGN, are essential in regulating interactions between astroglia and neurons. We further discovered that brain organoids derived from human embryonic stem cells (hESCs) harboring the autism-associated NLGN3 R451C mutation exhibit increased astrogliogenesis. Notably, the NLGN3 R451C astroglia demonstrate enhanced branching, indicating a more intricate morphology. Interestingly, our RNA sequencing data suggest that these mutant astroglia significantly upregulate pathways that support neural functions when compared to isogenic wild-type astroglia. Our findings establish a novel astroglia-enriched organoid model, offering a valuable platform for probing the roles of human astroglia in brain development and related disorders.
2024-12-08 | GSE283484 | GEO
Project description:Astroglia are the most abundant cell type in the central nervous system. They play essential roles in the homeostasis of the CNS. Astroglia are extremely diverse. In Amyotrophic Lateral Sclerosis (ALS) astroglia in spinal cord undergo dramatic transcriptomic dysregulation. However there is little to no data on the effects that cortical astroglia undergo during ALS pathogenesis. In this study we isolated pure cortical astroglia in end stage ALS mice. We performed microarray analysis and discovered dysregulated pathways and genetic markers. This may serve as a database for scientists to understand the effects that abnormal cortical astroglia have on cortical motor neurons and overall ALS pathology.
2019-04-30 | GSE111031 | GEO
Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder that threatens to reach epidemic proportions as our population ages. Although much research has examined molecular pathways associated with AD, relatively few studies have focused on critical early stages. Our prior microarray study correlated gene expression in human hippocampus with AD markers. Results suggested a new model of early-stage AD in which pathology spreads along myelinated axons, orchestrated by upregulated transcription and epigenetic factors related to growth and tumor suppression (Blalock et al., 2004). However, the microarray analyses were performed on RNA from fresh frozen hippocampal tissue blocks containing both gray and white matter, potentially obscuring region-specific changes. In the present study, we used laser capture microdissection to exclude major white matter tracts and selectively collect CA1 hippocampal gray matter from formalin-fixed, paraffin-embedded (FFPE) hippoc ampal sections of the same subjects assessed in our prior study. Microarray analyses of this gray matter-enriched tissue revealed many correlations similar to those seen in our prior study, particularly for neuron-related genes. Nonetheless, in the laser-captured tissue, we found a striking paucity of the AD-associated epigenetic and transcription factor genes that had been strongly overrepresented in the prior tissue block study. In addition, we identified novel pathway alterations that may have considerable mechanistic implications, including downregulation of genes stabilizing ryanodine receptor Ca2+ release and upregulation of vascular development genes. We conclude that FFPE tissue can be a reliable resource for microarray studies, that upregulation of growth-related epigenetic/ transcription factors with incipient AD is predominantly localized to white matter, further supporting our prior findings and model, and that alterations in vascular and ryanodine receptor-relat ed pathways in gray matter are closely associated with incipient AD.
2011-08-01 | GSE28146 | GEO
Project description:Connexin (Cx)30, which forms gap junction interconnecting astrocytes, regulates cell adhesion and migration and modulates glutamate transport. The expression levels of Cx30 are known to be upregulated on the activated astroglia at CNS inflammation lesion, including mutant-SOD1 transgenic ALS model mice spinal cord lesion. We aimed to clarify the role of Cx30 in mSOD1-transgenic mice. Cx30 was highly expressed in the pre-clinical stage of mSOD1-Tg mice. Cx30-knockout mSOD1 mice showed a delayed onset and tended to extend the survival period (log-rank, p = 0.09). At the progressive and end stages, anterior horn cells were more preserved in Cx30-knockout mSOD1 mice. Additionally, dorsal horn cells were kept more in Cx30-knockout mSOD1 mice at all stages. In the lesion of Cx30-knockout mSOD1 mice, GFAP and C3 positive inflammatory astroglia were decreased. Further, in Cx30-knockout mSOD1 mice, the amount of NOS2 protein at the end stage and the amount of Cx43 protein at the pre-clinical stage were smaller than in mSOD1 mice. These findings indicated reduced expression of astroglial Cx30 in the early stage of ALS model mice protects neurons by the attenuation of glial inflammation.
2022-09-24 | GSE213844 | GEO