Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

In vivo response of microglia to Aβ and prostaglandin-E2 EP2 receptor signaling

ABSTRACT: Microglia, the innate immune cells of the central nervous system, perform critical inflammatory and non-inflammatory functions to maintain homeostasis and normal neural function. However in Alzheimer’s disease (AD), these beneficial functions become progressively impaired, contributing to synapse and neuron loss and cognitive impairment. The inflammatory cyclooxygenase-PGE2 pathway, including the PGE2 receptor EP2, is implicated in AD development, both in human epidemiology and in transgenic models of AD. To test the transcriptional responses of EP2-deficient microglia to Aβ in vivo, we used mice in which the EP2 receptor is conditionally deleted in microglia using the CD11b-Cre transgene and floxed alleles of the EP2 gene. By injecting these mice with Aβ ICV and isolating microglia from the brains, we have been able to establish the transcriptional response of microglia to Aβ in vivo and test how EP2 deletion in microglia affects this response.

ORGANISM(S): Mus musculus

PROVIDER: GSE57181 | GEO | 2015/02/20

SECONDARY ACCESSION(S): PRJNA245856

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

In vivo response of microglia to Aβ and prostaglandin-E2 EP2 receptor signaling

Project description:Microglia, the innate immune cells of the central nervous system, perform critical inflammatory and non-inflammatory functions to maintain homeostasis and normal neural function. However in Alzheimer’s disease (AD), these beneficial functions become progressively impaired, contributing to synapse and neuron loss and cognitive impairment. The inflammatory cyclooxygenase-PGE2 pathway, including the PGE2 receptor EP2, is implicated in AD development, both in human epidemiology and in transgenic models of AD. To test the transcriptional responses of EP2-deficient microglia to Aβ in vivo, we used mice in which the EP2 receptor is conditionally deleted in microglia using the CD11b-Cre transgene and floxed alleles of the EP2 gene. By injecting these mice with Aβ ICV and isolating microglia from the brains, we have been able to establish the transcriptional response of microglia to Aβ in vivo and test how EP2 deletion in microglia affects this response. 8 month-old C57BL/6 mice, of the genotype CD11b-Cre; EP2+/+ or CD11b-Cre; EP2lox/lox, were injected I.C.V. with either Aβ or vehicle. 48 hours after injection, the mice were sacrificed and transcardially perfused with cold heparinized 0.9% NaCl. Brains were then removed from the mice and pooled, two brains of the same genotype per sample, to ensure adequate cell and RNA yield. The brains were then enzymatically dissociated for microglia isolation using the Neural Tissue Dissociation Kit (P), MACS Separation Columns (LS), and magnetic CD11b Microbeads from Miltenyi Biotec according to the manufacturer's protocol. Immediately after isolating the microglia, RNA was extracted from the cells for microarray analysis.

2015-02-20 | E-GEOD-57181 | biostudies-arrayexpress

Microglial response to Aβ and prostaglandin-E2 EP4 receptor activation

Project description:A persistent and non-resolving inflammatory response to accumulating Aβ peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aβ peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many pro-inflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aβ-induced inflammation represent a relatively unexplored area. Here we hypothesized that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aβ42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aβ42-induced inflammatory factors and potentiated phagocytosis of Aβ42. Microarray analysis was performed and demonstrated that EP4 stimulation broadly opposed Aβ42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors.

2014-04-25 | GSE55627 | GEO

Inhibition of PGE2-EP2/EP4 signaling elicits anti-tumor immunity through reprograming of inflammatory myeloid cells and suppression of mRegDC-Treg axis

Project description:The discovery of immune checkpoint inhibitor (ICI) has highlighted the clinical importance of immune evasion in cancer. However, only a fraction of cancer patients show response to ICI, raising a question on immune suppression mechanisms other than immune checkpoint. In this study, we examined the role of the lipid inflammatory mediator PGE2 in immune evasion of the ICI-insensitive Lewis Lung Carcinoma line 1 (LLC1) mouse model. Inhibition of PGE receptors, EP2 and EP4, significantly suppressed tumor growth through the modulation of host immune cells. Single cell RNA-sequencing analysis revealed that EP2/4 inhibition elicited anti-tumor immunity through the reprogramming of inflammatory myeloid cells by downregulating expression of genes in NFB signaling and actions and suppression of the mregDC-regulatory T cell axis by downregulating genes associated with regulatory T cell recruitment and activation. Taken together, our work suggests that PGE2-EP2/EP4 signaling induces proinflammatory myeloid and tolerogenic lymphoid environments in ICI-insensitive tumors, which is amenable to EP2 and EP4 inhibitors..

2022-06-14 | GSE169688 | GEO

T cell-intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic Th17 cell-driven inflammation

Project description:IL-23 induces ptgs2 encoding cyclooxygenase 2 in Th17 cells and produces PGE2, which acts back on PGE2 receptors EP2 and EP4 in these cells and enhances IL-23-induced expression of an IL-23 receptor subunit gene, Il23r, by activating STAT3, CREB1 and NF-κB through cAMP-protein kinase A signaling. This PGE2 signaling also induces expression of various inflammation-related genes, which possibly function in Th17 cell-mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A+ and IL-17A+IFN-γ+ pathogenic Th17 cells and abolished skin inflammation in IL-23-induced psoriasis mouse model. Analysis of human psoriatic skin biopsies shows positive correlation between PGE2 signaling and the IL-23/Th17 pathway.

2021-02-23 | GSE167248 | GEO

The major risk factors for Alzheimer’s disease: Age, Sex and Genes, modulate the microglia response to Aβ plaques (CDEP)

Project description:Microglia are involved in Alzheimer’s disease (AD) by adopting activated phenotypes. How ageing in the absence or presence of β-amyloid (Aβ) deposition in different brain areas affects this response and whether sex and AD risk genes are involved, remains however largely unknown. Here we analyzed the gene expression profiles of more than 10,000 individual microglia cells isolated from cortex and hippocampus of male and female AppNL-G-F at 4 different stages of Aβ deposition and in age-matched control mice. We demonstrate that microglia adopt two major activated states during normal aging and after exposure to amyloid plaques. One of the responses (activated response microglia, ARM) is enhanced in particular by amyloid plaques and is strongly enriched with AD risk genes. The ARM response is not homogeneous, as subgroups of microglia overexpressing MHC type II and tissue repair genes (Dkk2, Gpnmb, Spp1) are induced upon prolonged Aβ exposure. Microglia in female mice advance faster in the activation trajectories. Similar activated states were also found in a second AD model and in human brain. We demonstrate that abolishing the expression of Apoe, the major genetic risk factor for AD, impairs the establishment of ARMs, while the second microglia response type, enriched for interferon response genes, remains unaffected. Our data indicate that ARMs are the converging point of multiple AD risk factors.

2019-04-23 | GSE127884 | GEO

The major risk factors for Alzheimer’s disease: Age, Sex and Genes, modulate the microglia response to Aβ plaques (KW)

2019-04-23 | GSE127892 | GEO

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer’s disease

Project description:Alzheimer's disease (AD) is associated with the formation of extracellular amyloid-β (Aβ) plaque, perturbing the mechanical properties of brain tissue. Microglia sense and integrate biochemical and mechanical cues in their local microenvironment, intimately linked with AD progress. However, little is known about how microglial mechanosensing pathways are implicated in AD pathogenesis. Gene Ontology (GO) analysis of the significantly down-regulated genes in Piezo1 conditional knockout microglia revealed a significant functional reduction in synapse organization, cell-substrate adhesion, and cytoskeleton system-based events (morphogenesis, migration, and endocytosis) in 5×FAD mice.

2022-03-26 | GSE199217 | GEO

MCG 101 tumors implanted on prostaglandin receptor EP2 wildtype and EP2 knockout mice

Project description:Wild type tumor cells, producing high levels of prostaglandin E2 (MCG101, EP2 +/+), were inoculated on EP2 knockout (EP2 -/-) and EP2 wild type (EP2 +/+) mice. Solid tumors were dissected into tumor- and tumor-stroma tissue compartments for RNA expression microarray screening, followed by metabolic pathway analyses. The study aims to evaluate simultaneous gene pathway expressions in separate tissue compartments, such as isolated tumor tissue and tumor stroma respectively.

2022-05-25 | GSE193098 | GEO

SELENOK-Dependent CD36 Palmitoylation Regulates Microglial Functions and Aβ Phagocytosis

Project description:Amyloid-beta (Aβ) is a key factor in the onset and progression of Alzheimer's disease (AD). Selenium (Se) compounds show promise in AD treatment. Here, we reveal that selenoprotein K (SELENOK), a selenoprotein involved in immune regulation and potentially related to AD pathology, plays a critical role in microglial immune response, migration, and phagocytosis. In vivo and in vitro studies corroborate that SELENOK deficiency inhibits microglial Aβ phagocytosis, exacerbating cognitive deficits in 5xFAD mice, which are reversed by SELENOK overexpression. Mechanistically, SELENOK is involved in CD36 palmitoylation through DHHC6, regulating CD36 localization to microglial plasma membranes and thus impacting Aβ phagocytosis. CD36 palmitoylation is reduced in the brains of AD patients and mice. Se supplementation promotes SELENOK expression and CD36 palmitoylation, enhancing microglial Aβ phagocytosis and mitigating AD progression. We have identified the regulatory mechanisms from Se-dependent selenoproteins to Aβ pathology, providing novel insights into potential therapeutic strategies involving Se and selenoproteins.

2024-02-29 | GSE255034 | GEO

Transcriptomic and functional analysis of Ab1-42 oligomer-stimulated human monocyte-derived microglia-like cells

Project description:Dysregulation of microglial function contributes to Alzheimer’s disease (AD) pathogenesis. Several genetic and transcriptome studies have revealed microglia specific genetic risk factors, and changes in microglia expression profiles in AD pathogenesis, viz. the human-Alzheimer’s microglia/myeloid (HAM) profile in AD patients and the disease-associated microglia profile (DAM) in AD mouse models. The transcriptional changes involve genes in immune and inflammatory pathways, and in pathways associated with Aβ clearance. Aβ oligomers have been suggested to be the initial trigger of microglia activation in AD. To study the direct response to Aβ oligomers exposure, we assessed changes in gene expression in an in vitro model for microglia, the human monocyte-derived microglial-like (MDMi) cells. We confirmed the initiation of an inflammatory profile following LPS stimulation, based on increased expression of IL1B, IL6, and TNFα. In contrast, the Ab1-42 oligomers did not induce an inflammatory profile or a classical HAM or DAM profile. Interestingly, we observed a specific increase in the expression of metallothioneins in the Aβ1-42 oligomer treated MDMi cells. Metallothioneins are involved in metal ion regulation, protection against reactive oxygen species, and have anti-inflammatory properties. In conclusion, our data suggests that Aβ1-42 oligomers may trigger a protective response both in vitro and in vivo.

2022-01-09 | GSE187452 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data