Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Neuronal accumulation of peroxidated lipids promotes demyelination and neurodegeneration though the activation of the microglial NLRP3 inflammasome

ABSTRACT: Peroxidated lipids accumulate in the presence of reactive oxygen species and are linked to neurodegenerative diseases. Here we found that neuronal ablation of Arf1, a small GTPase important for lipid homeostasis, promoted the accumulation of peroxidated lipids, lipid droplets and ATP in the mouse brain and led to neuroinflammation, demyelination, and neurodegeneration, mainly in the spinal cord and hindbrain. Ablation of Arf1 in cultured primary neurons led to an increase in peroxidated lipids in co-cultured microglia, the activation of the microglial NLRP3 inflammasome, and the release of inflammatory cytokines in an APOE-dependent manner. Deleting the Nlrp3 gene rescued the neurodegenerative phenotypes in the neuronal Arf1-ablated mice. We also observed a reduction in Arf1 in human brain tissue from amyotrophic lateral sclerosis and multiple sclerosis patients. Together, our results uncover a previously unrecognized role of peroxidated lipids released from damaged neurons in the activation of a neurotoxic microglial NLRP3 pathway that may play a role in human neurodegeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE183483 | GEO | 2021/09/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Neuronal accumulation of peroxidated lipids promotes demyelination and neurodegeneration though the activation of the microglial NLRP3 inflammasome

Project description:Neuronal accumulation of peroxidated lipids promotes demyelination and neurodegeneration though the activation of the microglial NLRP3 inflammasome

| PRJNA760949 | ENA

UBQLN2 Governs Lipid Metabolism Linked to Neurodegeneration in ALS/FTD

Project description:Missense mutations in UBQLN2, a protein quality control factor, are associated with neurodegenerative diseases amyotrophic lateral sclerosis (ALS) overlapping with frontotemporal dementia (FTD). The mechanisms by which these mutations lead to neurodegeneration are not fully understood. Here we describe a critical role for UBQLN2 in regulating cellular lipid metabolism, which is crucial for cell survival under nutrient stress. The stress dependent regulation of lipid metabolism by UBQLN2 is mediated by ILVBL, a UBQLN2 substrate and a key enzyme in lipid turnover. The function of UBQLN2 in promoting ILVBL degradation and maintaining intracellular lipids was compromised by ALS/FTD-linked mutations in UBQLN2. As a result of the lipid dysregulation, synaptic vesicles were deficient and neuronal death was exacerbated in mutant UBQLN2 transgenic mice or human iPSCs derived motor neurons and cortical organoids. Replenishing lipids or restoring UBQLN2 function could reverse the deficits in the UBQLN2 mutant neurons under nutrient stress. Our study reveals UBQLN2 essential role in lipid metabolism and suggests metabolic imbalance underlying ALS/FTD and related neurodegenerative conditions.

2023-12-27 | MSV000093732 | MassIVE

Repeated systemic challenge with lipopolysaccharides induces dopaminergic neurodegeneration in the brain by activation of the complement-phagosome pathway

Project description:Systemic inflammatory reactions mediated by chronic infections activate microglia in the central nervous system (CNS) and have been postulated to exacerbate neurodegenerative diseases. We now demonstrate in vivo that repeated systemic challenge of mice with bacterial lipopolysaccharides (LPS) maintains an elevated microglial inflammatory response and triggers neurodegeneration. Repeated chronic intraperitoneal application of LPS over four consecutive days induced loss of dopaminergic neurons in the substantia nigra, a process that was accompanied by decreased levels of dopamine in the striatum. In contrast, total cumulative LPS dose given intraperitoneally within a single acute application did not induce a decrease in dopamine levels nor neurodegeneration. Mice that received repeated systemic LPS application showed increased microglial activation, elevated production of proinflammatory cytokines and activation of the classical complement and its associated phagosome pathway in the brain. Loss of dopaminergic neurons induced by repeated systemic LPS application was rescued in complement C3 deficient mice, confirming an involvement of the complement system in neurodegeneration. Thus, our data demonstrate that repeated systemic exposure to bacterial LPS induces a microglial phagosomal inflammatory response, leading to complement-dependent damage of dopaminergic neurons.

2014-07-11 | E-MTAB-1770 | biostudies-arrayexpress

RNA-seq to investigate sex-dependent changes in microglia in Cst7 knockout mice crossed with a mouse model of amyloid-driven Alzheimer's Disease

Project description:Microglial endolysosomal dysfunction is strongly implicated in neurodegeneration. Transcriptomic studies show that a microglial state characterised by a set of genes involved in endolysosomal function is induced in both mouse Alzheimer’s Disease (AD) models and in human AD brain, and that the onset of this state is emphasised in females. Cst7 (Cystatin F) is among the most highly unregulated genes in these microglia. However, the sex-specific function of Cst7 in neurodegenerative disease is not understood. Here, we crossed Cst7 -/- mice with the App NL-G-F mouse to test the role of Cst7 in a model of amyloid-driven AD.

2023-11-22 | E-MTAB-13360 | biostudies-arrayexpress

Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration

Project description:Microglia are brain immune cells that constantly survey their environment to maintain homeostasis. Enhanced microglial reactivity and proliferation are typical hallmarks of neurodegenerative diseases. Whether specific disease-linked microglial subsets exist during the entire course of neurodegeneration, including the recovery phase, is currently unclear. Taking a single-cell RNA-sequencing approach in a susceptibility gene-free model of nerve injury, we identified a microglial subpopulation that upon acute neurodegeneration shares a conserved gene regulatory profile compared to previously reported chronic and destructive neurodegeneration transgenic mouse models. Our data also revealed rapid shifts in gene regulation that defined microglial subsets at peak and resolution of neurodegeneration. Finally, our discovery of a unique transient microglial subpopulation at the onset of recovery may provide novel targets for modulating microglia-mediated restoration of brain health.

2018-08-25 | GSE90975 | GEO

Cell autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS microglia contributes to neurodegeneration

Project description:The most common genetic mutation found in familial and sporadic amyotrophic lateral sclerosis (ALS), as well as fronto-temporal dementia (FTD), is a repeat expansion in the C9orf72 gene. C9orf72 is highly expressed in human myeloid cells, and although neuroinflammation and microglial pathology are widely found in ALS/FTD, the underlying mechanisms are poorly understood. Here, using human induced pluripotent stem cell-derived microglia-like cells (hiPSC-MG) harbouring C9orf72 mutation (mC9-MG) together with gene-corrected isogenic controls (isoC9-MG) and C9ORF72 knock-out hiPSC-MG (C9KO-MG), we show that reduced C9ORF72 protein is associated with impaired phagocytosis and an exaggerated inflammatory response upon stimulation with lipopolysaccharide, driven by sustained activation of NLRP3 inflammasome and NF-kB signalling. Analysis of the hiPSC-MG C9ORF72 interactome revealed an association of C9ORF72 with key regulators of autophagy, a process involved in the homeostatic regulation of the innate immune response. We found impaired initiation of autophagy in C9KO-MG and mC9-MG. Furthermore, through motor neuron-microglial (MN-MG) co-culture studies, we identified that autophagy deficit in mC9-MG led to increased vulnerability of C9 MNs to excitotoxic stimulus. Pharmacological activation of autophagy ameliorated the sustained activation of NLRP3 inflammasome and NF-B signalling, reversed the phagocytic deficit found in mC9-MG and also reduced MN death in MN-MG co-cultures. We validated these findings in blood-derived macrophages from people with C9orf72 mutation. Our results reveal an important role for C9ORF72 in regulating microglial immune homeostasis and identify dysregulation in human myeloid cells as a contributor to neurodegeneration in ALS/FTD

2023-03-02 | PXD032320 | Pride

SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1beta

Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1Î² selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1Î² transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1Î². Consistent with our findings in mice, selective hypomethylation of IL-1Î² at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia

2014-10-01 | E-GEOD-56452 | biostudies-arrayexpress

The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases V

Project description:Microglia play a pivotal role in the maintenance of brain homeostasis, but lose their homeostatic function during the course of neurodegenerative disorders. We identified a specific APOE-dependent molecular signature in microglia isolated from mouse models of amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer’s disease (SOD1, EAE and APP-PS1) and in microglia surrounding neuritic A-plaques in human Alzheimer’s disease brain. This is mediated by a switch from a (M0)-homeostatic to (MGnD)-neurodegenerative phenotype following phagocytosis of apoptotic neurons via the TREM2-APOE pathway. TREM2 induces APOE signaling which is a negative regulator of the transcription program in M0-homeostatic microglia. Targeting the TREM2-APOE pathway restores the M0-homeostatic signature of microglia in APP-PS1 and SOD1 mice and prevents from neuronal loss in an acute model of neurodegeneration. In SOD1 mice, TREM2 regulates MGnD in a gender-dependent manner. APOE-mediated MGnD microglia lose their tolerogenic function. Taken together, our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target to restore homeostatic microglia.

2017-09-19 | GSE102563 | GEO

The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases IV

2017-09-19 | GSE102562 | GEO

The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases VI

2017-09-19 | GSE102564 | GEO