Expression data from primary cultured microglia from Fosb-null mouse
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Yusaku Nakabeppu
PROVIDER: E-GEOD-40714 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and ΔFosb, encoding full-length FOSB and ΔFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and ΔFosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate-induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no change in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression.
2014-04-18 | GSE40714 | GEO
Project description:To examine fosB regulation of neurogenesis, depression and epilepsy, we compared the gene expression profiles of wild type, fosBd/d and fosB-null mice by microarray analysis. Microarray analysis revealed that genes related to neurogenesis, depression and epilepsy are altered in the hippocampus of fosB-null mice.
2013-01-01 | GSE37056 | GEO
Project description:To examine fosB regulation of neurogenesis, depression and epilepsy, we compared the gene expression profiles of wild type, fosBd/d and fosB-null mice by microarray analysis. Microarray analysis revealed that genes related to neurogenesis, depression and epilepsy are altered in the hippocampus of fosB-null mice. Total RNA from the hippocampus of wild-type, fosBd/d and fosB-null mice was prepared using ISOGEN and RNeasy Mini kits. For DNA microarray experiments, total RNA (100ng) was added to poly-A control and treated with WT Expression Kit. cDNA was labeled using WT terminal labeling kit and hybridized with Affymetrix GeneChip Mouse Gene 1.0 ST platform (GPL6246).
2013-01-01 | E-GEOD-37056 | biostudies-arrayexpress
Project description:Microglial dysfunction is a key pathological feature of Alzheimer´s disease (AD), but little is known about proteome-wide changes in microglia during the course of AD pathogenesis and their consequences for microglial function. Here, we performed an in-depth proteomic characterization of microglia in two AD mouse models, the overexpression APPPS1 and the knock-in AppNL-G-F (APP-KI) model. Proteome changes were followed from pre-deposition to early, middle and advanced stages of amyloid plaque pathology, revealing a large panel of Microglial Amyloid Response Proteins (MARPs) that reflect a heterogeneity of microglial alterations triggered by Adeposition. We demonstrate that the occurrence of MARPs coincided with the deposition of fibrillar A, recruitment of microglia to amyloid plaques and phagocytic dysfunction. While the proteomic and functional microglial changes were already markedly seen in 3 months old APPPS1 mice, they were delayed in the APP-KI model that generates substantially less fibrillar A. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy.
2020-06-09 | PXD016075 | Pride
Project description:Traumatic brain injury (TBI) triggers neuroinflammatory cascades mediated by microglia, which promotes tissue repair in the short-term. These cascades may exacerbate TBI-induced tissue damage and symptoms in the months to years post-injury. However, the progression of the microglial function across time post-injury and whether this differs between biological sexes is not well understood. In this study, we examined the microglial proteome in the days (3- and 7-days) to 1 month (28 days) after a midline fluid percussion injury (mFPI) in male and female mice using label-free quantitative proteomics. We identified a reduction in microglial proteins involved with clearance of neuronal debris via phagocytosis at 3- and 7-days post-injury. At 28 days post-injury pro-inflammatory proteins were decreased and anti-inflammatory proteins were increased in microglia. These results indicate a reduction in microglial clearance of neuronal debris in the days post-injury with a shift to anti-inflammatory function by 1 month. The changes in the microglial proteome that occurred across time post-injury did not differ between biological sexes. However, we did identify an increase in microglial proteins related to pro-inflammation as well as insulin and estrogen signalling in males compared with female mice that occurred with or without a brain injury. Although microglial response was similar between males and females up to 1 month following TBI, biological sex differences in the basal microglial proteome has implications for the efficacy of treatment strategies targeting the microglial response post-injury.
2023-03-11 | PXD033628 | Pride
Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4
2015-11-04 | E-GEOD-74614 | biostudies-arrayexpress
Project description:Background Proteomic characterization of microglia has been limited by low yield and contamination by non-microglial proteins by magnetic-activated cell sorting (MACS) enrichment strategies. To determine whether a fluorescent-activated cell sorting (FACS)-based strategy overcomes these limitations, we compared microglial proteomes of MACS and FACS-based purified CD11b+ microglia in order to identify core sets of microglial proteins in adult mouse brain tissue. Results Quantitative multiplex proteomics by tandem mass tag mass spectrometry (TMT-MS) of MACS-enriched (N = 5) and FACS-purified (N = 5) adult wild-type CD11b+ microglia identified 1,791 proteins, of which 953 were differentially expressed indicating significant differences between both approaches. While the FACS-purified microglia proteome was enriched with cytosolic, endoplasmic reticulum and ribosomal proteins involved in protein metabolism and immune system functions, the MACS-enriched microglia proteome was enriched with proteins related to mitochondrial function and synaptic transmission. As compared to MACS, the FACS microglial proteome showed strong enrichment for canonical microglial proteins while neuron, astrocyte, and oligodendrocyte proteins were decreased. Interestingly, we observed enrichment of endothelial specific proteins in the FACS microglia proteome. By comparing FACS-purified microglia proteomes with transcriptomes, we observed highly concordant as well as highly discordant proteins that were abundant at the protein level but low at the transcript level. Conclusions We demonstrate that TMT-MS proteomics of FACS-purified adult microglia is superior to column-based enrichment approaches, resulting in purer and highly-enriched microglial proteomes. We also define core sets of highly-abundant adult microglial proteins including Moesin (Msn) that can guide future studies.
2020-05-11 | PXD015652 | Pride
Project description:∆FosB epigenetically regulates target gene expression; however, whether ∆FosB targets the same genes when induced by recurrent seizures in different neurological conditions like Alzheimer's disease (AD) is unclear. We performed hippocampal ChIP-sequencing to identify ∆FosB target genes in APP mice, a model of AD, and in pilocarpine-treated wildtype mice (Pilo mice), a model of epilepsy. Functional domains modulated by ∆FosB target genes are expanded and diversified in APP mice and in Pilo mice (vs respective controls), and primarily involve neuronal excitability and neurotransmission, neurogenesis, chromatin remodeling, and cellular stress and immunity. To identify genes bound by ∆FosB regardless of seizure etiology, we focused on the 442 ∆FosB target genes in both APP and Pilo mice (not respective controls), which related to pathways including membrane potential regulation, glutamatergic signaling, complement activation, neuron-glia population maintenance, and chromatin dynamics. RNA-sequencing and RT-qPCR in independent mice detected altered expression of several ∆FosB targets shared in APP and Pilo mice. Our findings indicate that seizure-induced ∆FosB can bind genes in seizure etiology-dependent patterns, but can also bind genes in patterns regardless of seizure etiology. Understanding factors that influence ∆FosB binding patterns could reveal novel insights into control of gene expression in disorders with recurrent seizures.
2020-04-16 | E-MTAB-8954 | biostudies-arrayexpress
Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.
2018-09-18 | PXD009137 | Pride
Project description:Amyloid-beta (Aβ) deposition is an initiating factor in Alzheimer´s disease (AD). Microglia are the brain immune cells that surround and phagocytose Aβ, but their phagocytic capacity declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating phagocytic function. Immunotherapies are currently pursued as therapeutic strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Aβ targeting ACI-24 vaccine in preventing the AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Aβ plaque load, amyloid plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, plaque-associated microglia had the tendency to be more activated post vaccination. The lower Aβ plaque load triggered by vaccination with ACI-24 was in concordance with the bulk transcriptomic analysis that revealed a reduction in the expression of several disease-associated microglial signatures. Accordingly, plaque-distant microglia displayed a more ramified morphology, supporting beneficial effects of the vaccination on bulk microglial phenotypes. Our study demonstrates that administration of the Aβ targeting vaccine, ACI-24, triggers protective microglial responses that translate into a reduction of AD pathology suggesting its use as a safe and cost effective AD therapeutic intervention.
2023-01-09 | PXD038665 | Pride