Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy
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ABSTRACT:
PROVIDER: PRJNA1055881 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27325144_1.fastq.gz | Fastqsanger.gz | |||
| SRR27325144_2.fastq.gz | Fastqsanger.gz | |||
| SRR27325145_1.fastq.gz | Fastqsanger.gz | |||
| SRR27325145_2.fastq.gz | Fastqsanger.gz | |||
| SRR27325146_1.fastq.gz | Fastqsanger.gz |
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Project description:Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. Here, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old wildtype mice, and in a mouse model of tauopathy. We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and tauopathy mice. These effects of NF-κB/NLRP3-targeting Nanoligomer treatment were associated with reduced glial cell activation in old wildtype mice, less pathology in tauopathy mice, favorable changes in transcriptome signatures of inflammation (reduced) and neuronal health (increased) in both mouse models, and no adverse systemic effects. Collectively, our results provide a basis for future translational studies targeting NF-κB/NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegenerative disease.
2024-02-07 | GSE251888 | GEO
Project description:Neuroinflammation is a key component of Alzheimer's disease (AD), and it may be driven by the activation of NFκB and NLRP3 signaling pathways. AD pathology, like amyloid-β, may exacerbate the activation of these pathways. We used a nucleic acid therapeutic (nanoligomer) cocktail targeting NFκB and NLRP3 to reduce inflamamtory signaling in aged wildtype mice and a transgenic mouse model of amyloid-β pathology (APP/PS1). Short-term (3 days) treatment reversed age- and amyloid-β-related gene sigantures, supporting the idea that this nanoligomer cocktail may have the potential to improve AD-related neuroinflammation and cognitive dysfunction.
2025-07-25 | GSE303458 | GEO
Project description:Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles in addition to neuroinflammation and changes in brain lipid metabolism. Recent findings have demonstrated that microglia are key drivers of neurodegeneration in tauopathy mouse models. A subset of microglia referred to as disease-associated microglia (DAM) display gene signatures signifying changes in proinflammatory signaling and lipid metabolism in mouse models of amyloid and tau pathology. Ch25h is a DAM gene encoding cholesterol 25-hydroxylase that produces 25-hydroxycholesterol (25HC), a known modulator of inflammation as well as lipid metabolism. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and 25HC there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory cytokine and chemokine signaling in microglia and restored sterol synthesis. Our results suggest a key role for Ch25h/25HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases.
2023-12-08 | GSE242896 | GEO
Project description:Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles in addition to neuroinflammation and changes in brain lipid metabolism. Recent findings have demonstrated that microglia are key drivers of neurodegeneration in tauopathy mouse models. A subset of microglia referred to as disease-associated microglia (DAM) display gene signatures signifying changes in proinflammatory signaling and lipid metabolism in mouse models of amyloid and tau pathology. Ch25h is a DAM gene encoding cholesterol 25- hydroxylase that produces 25-hydroxycholesterol (25HC), a known modulator of inflammation as well as lipid metabolism. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and the resultant reduction in 25HC there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice, which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory cytokine and chemokine signaling in microglia and restored sterol synthesis. Our results suggest a key role for Ch25h/25HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases.
2024-02-23 | GSE250277 | GEO
Project description:Objective: The protective components ACE2/Ang(1-7)/MasR of the renin-angiotensin system has been verified to play a role in Alzheimer's disease (AD). Our previous study revealed that enhancement of brain ACE2 activity, an important effector of RAS, by diminazene aceturate (DIZE) ameliorated Alzheimer's disease-like neuropathology and attenuated neuroinflammation in the brain of SAMP8 mice. However, the potential molecular mechanisms by which DIZE modulates neuroinflammation in AD remain unclear. Materials and Methods: APP/PS1 mice were injected intraperitoneally with DIZE (once a day for 30 consecutive days). Cognitive functions, neuronal and synaptic integrity, and inflammation-related markers were assessed by Morris water maze, Nissl staining, Western blot and ELISA, respectively. Since astrocytes played a crucial role in AD-related neuroinflammation whilst miRNAs were reported to participate in modulating inflammatory responses, astrocytes of APP/PS1 mice were then isolated for high-throughput miRNAs sequencing to identify the most differentially expressed miRNA following DIZE treatment. Afterward, the downstream pathway of this miRNA in the anti-inflammatory action of DIZE was investigated using primary astrocytes. Results: The results showed that DIZE alleviated cognitive impairment and neuronal and synaptic damage in APP/PS1 mice. Simultaneously, DIZE suppressed the secretion of pro-inflammatory cytokines and the expression of NLRP3 inflammasome. Importantly, miR-224-5p was significantly up-regulated in the astrocytes of APP/PS1 mice treated by DIZE, and NLRP3 is one of the targets of miR-224-5p. Upregulation of miR-224-5p inhibited the expression of NLRP3 in Aβ1–42-stimulated cells, whereas miR-224-5p downregulation reversed this effect. Furthermore, the inhibition of miR-224-5p could reverse the inhibitory effect of DIZE on astrocytic NLRP3 inflammasome. Conclusion: These results firstly suggested that DIZE inhibits astrocyte-mediated neuroinflammation via miR-224-5p/NLRP3 pathway. Moreover, these results reveal the underlying mechanisms by which DIZE inhibits neuroinflammation under AD condition and uncovers the potential of DIZE in AD treatment.
2023-04-26 | GSE199028 | GEO
Project description:Reducing neuroinflammation, a main hallmark of brain aging and neurodegenerative diseases, is a promising strategy for improving cognitive function in these settings. The nucleoside reverse transcriptase inhibitor 3TC (Lamivudine) has been reported to improve cognitive function in old wild-type mice and in multiple mouse models of neurodegenerative disease, but the underlying mechanisms have not been comprehensively investigated. In the current study, we used transcriptomics to broadly characterize the effects of long-term supplementation with a human-equivalent therapeutic dose of 3TC on the hippocampal transcriptome in male and female rTg4510 mice (a commonly studied model of tauopathy-associated neurodegeneration). We found that tauopathy increased hippocampal transcriptomic signatures of neuroinflammation/immune activation, but 3TC treatment reversed many of these transcriptome changes. We also found that 3TC mitigated tauopathy-associated activation of several key transcription factors that contribute to neuroinflammation and immune activation, and several of these changes were correlated with improved recognition memory performance.Our findings suggest that 3TC exerts beneficial effects on the hippocampus in the context of tauopathy by modulating pathways associated with inflammation and immune response.
2024-05-13 | GSE243650 | GEO
Project description:Microglial 25-hydroxycholesterol mediates neuroinflammation and neurodegeneration in a tauopathy mouse model.
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Project description:Objective: Emerging evidence suggested that brain angiotensin-(1-7) (Ang-(1-7)) deficiency contributed to the pathogenesis of Alzheimer’s disease (AD). Meanwhile, our previous studies revealed that restoration of brain Ang-(1-7) levels provided neuroprotection by inhibition of inflammatory responses during AD progress. However, the potential molecular mechanisms by which Ang-(1-7) modulates neuroinflammation remain unclear. Materials and Methods: APP/PS1 mice were injected intraperitoneally with AVE0991 (a nonpeptide analogue of Ang-(1-7)) once a day for 30 consecutive days. Cognitive functions, neuronal and synaptic integrity, and inflammation-related markers were assessed. Since astrocytes played a crucial role in AD-related neuroinflammation whilst long noncoding RNAs (lncRNAs) were reported to participate in modulating inflammatory responses, astrocytes of APP/PS1 mice were then isolated for high-throughput lncRNA sequencing to identify the most differentially expressed lncRNA following AVE0991 treatment. Afterward, the downstream pathway of this lncRNA in the anti-inflammatory action of AVE0991 were investigated using primary astrocytes. Results: The protection of AVE0991 against cognitive impairment and neuronal and synaptic damage in APP/PS1 mice was confirmed. For the first time, we demonstrated that AVE0991 suppressed astrocytic NLRP3 inflammasome-mediated neuroinflammation via a lncRNA SNHG14-dependent manner. SNHG14 acted as a sponge of miR-223-3p while NLRP3 represented a direct target of miR-223-3p in astrocytes. In addition, miR-223-3p participated in the AVE0991-induced suppression of astrocytic NLRP3 inflammasome. Conclusion: These results suggest that AVE0991 inhibits astrocyte-mediated neuroinflammation via SNHG14/miR-223-3p/NLRP3 pathway. Moreover, these results reveal the underlying mechanisms by which Ang-(1-7) inhibits neuroinflammation under AD condition and uncovers the potential of its nonpeptide analogue AVE0991 in AD treatment.
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Project description:Blood-brain barrier (BBB) disintegration emerges as a significant contributor to neuroinflammation; however, the biological processes governing BBB permeability under physiological conditions remain unclear. Here, we examined the potential role of NLRP3 inflammasome in BBB disruption following peripheral inflammatory challenges. Systemic lipopolysaccharide administration caused an NLRP3-dependent increase in BBB permeability and myeloid cell infiltration into the brain. Using a cell-specific, hyperactive NLRP3-expressing mouse model, we found that microglial NLRP3 activation is crucial for peripheral inflammation-induced BBB disruption. In contrast, NLRP3 and microglial gasdermin D (GSDMD) deficiency remarkably attenuated lipopolysaccharide-induced BBB breakdown. Notably, IL-1 was unnecessary for this NLRP3-GSDMD-mediated BBB disruption. Instead, microglial NLRP3-GSDMD axis specifically upregulates CXCL chemokine around BBB via producing GDF-15, recruiting Cxcr2-containing neutrophils into the brain. Neutrophil depletion and Cxcr2 blockade significantly reduced NLRP3-mediated BBB impairment. Collectively, our findings unveiled the significant role of NLRP3-driven chemokine production for BBB disintegration, suggesting a potential therapeutic target to mitigate neuroinflammation.
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