An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer’s disease
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ABSTRACT:
PROVIDER: PRJNA679618 | ENA |
REPOSITORIES: ENA
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Project description:Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism pathway and have anti-inflammatory activities. However, their efficacy is limited due to their rapid hydrolysis by the soluble epoxide hydrolase (sEH). We report that sEH is predominantly expressed in astrocytes and its concentrations are elevated in postmortem brain tissue from AD patients and in the 5xFAD -amyloid mouse model of AD. The amount of sEH expressed in AD mouse brains correlated with a reduction in brain EpFA concentrations. Using a specific small molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report that TPPU treatment protected AD mice against LPS-induced inflammation in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation. This was associated with reduced β-amyloid pathology and improved synaptic integrity and cognitive function on two behavioral tests. Importantly, TPPU treatment correlated with an increase in EpFA concentrations in the brains of 5xFAD mice, demonstrating brain penetration and target engagement. These findings support further investigation of TPPU as a potential therapeutic agent for the treatment of AD.
2020-11-20 | GSE161848 | GEO
Project description:Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer’s disease mouse model
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Project description:Deposition of amyloid beta (Aβ) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer’s disease (AD). In recent years, impairment of autophagy has been found to be another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aβ pathology and glial cell-mediated neuroinflammation. Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aβ and decreased AD-associated neuroinflammation. A subsequent proteome analysis of isolated microglia confirmed the anti-inflammatory and revealed cytoskeletal effects of spermidine in APPPS1 mice. Our data highlight that the autophagy activator spermidine holds the potential to enhance Aβ degradation and to counteract microglia-mediated neuroinflammation in AD pathology.
2022-07-04 | PXD034638 | Pride
Project description:Deposition of amyloid beta (Aβ) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer’s disease (AD). In recent years, impairment of autophagy has been found to be another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aβ pathology and glial cell-mediated neuroinflammation. Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aβ and decreased AD-associated neuroinflammation during disease progression. Mechanistically, single nuclei sequencing revealed AD-associated microglia to be the main target of spermidine. This microglia population was characterized by increased AXL levels and expression of genes implicated in cell migration and phagocytosis. Our data highlight that the autophagy activator spermidine holds the potential to enhance Aβ degradation and to counteract glia-mediated neuroinflammation in AD pathology.
2022-07-04 | GSE206202 | GEO
Project description:Several studies have indicated that the cannabinoid receptor 2(CB2) plays an important role in neuroinflammation associated with Alzheimer’s disease (AD) progression. The present study examined the role of CB2 in microglia activation in vitro as well as characterizing the neuroinflammatory process in a transgenic mouse model ofAD (APP/PS1mice). We demonstrate that microglia harvested from CB2-/- mice were less responsive to pro-inflammatory stimuli than CB2+/+ microglia based on the cell surface expression of ICAM and CD40 and the release of chemokines and cytokines CCL2, IL-6, and TNFα. Transgenic APP/PS1 mice lacking CB2showed reduced percentages of microglia and infiltrating macrophages. Furthermore, they showed lowered expression levels of pro-inflammatory chemokines and cytokine in the brain, as well as diminished concentrations of soluble Aβ 40/42.The reduction in neuroinflammation did not affect spatial learning and memory in APP/PS1*CB2-/- mice. These data suggest a role for the CB2 in Alzheimer’s disease-associated neuroinflammation independent of influencing Aβ mediated pathology and cognitive impairment.
2017-01-09 | GSE60903 | GEO
Project description:Diet is a modifiable risk factor for cardiovascular disease (CVD) and dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain microvasculature. The objective of our study was to determine the molecular effects of a HGD on hippocampal microvessels and cognitive function, and to determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/inflammation/oxidation effects reversible by t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer’s dementia.
2021-12-07 | GSE185057 | GEO
Project description: Not available
| S-EPMC7784555 | biostudies-literature
Project description:Neuroinflammation plays a role in the progression of several neurodegenerative disorders. We used a lipolysaccharide (LPS) model of neuroinflammation to characterize the gene expression changes underlying the inflammatory and behavioral effects of neuroinflammation. A single intracerebroventricular injection of LPS (5 ug) was administered into the lateral ventricle of mice and, 24 hours later, we examined gene expression in the cerebral cortex and hippocampus using microarray technology. Gene Ontology (GO) terms for inflammation and the ribosome were significantly enriched by LPS, whereas GO terms associated with learning and memory had decreased expression. We detected 224 changed transcripts in the cerebral cortex and 170 in the hippocampus. Expression of Egr1 (also known as Zif268) and Arc, two genes associated with learning and memory, was significantly lower in the cortex, but not hippocampus, of LPS-treated animals. Overall, altered expression of these genes may underlie some of the inflammatory and behavioral effects of neuroinflammation. Mice were given intracerebroventricular injections of saline vehicle (n = 4) or lipopolysaccharide (n = 4). Twenty-four hours later, we dissected the hippocampus and cerebral cortex and processed the tissue for microarray analysis. Gene expression changes observed in the microaray data were validated with quantitative real-time PCR.
2008-11-01 | E-GEOD-12284 | biostudies-arrayexpress
Project description:Activation of the STING-dependent type I interferon response reduces microglial reactivity and neuroinflammation
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Project description:Neuroinflammation and activation of innate immunity are pathological hallmarks of Alzheimer’s disease (AD). In contrast, very few studies have examined the impact of the adaptive immune system in AD pathogenesis. In this study, we find that genetic deletion of peripheral immune populations significantly accelerates amyloid pathogenesis, worsens neuroinflammation, and alters microglial activation state. We used microarray analysis to profile gene expression underlying genotype related changes at the cellular level in the context of AD .
2016-03-03 | GSE77574 | GEO