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Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway ( nascent RNA-Seq )

ABSTRACT: Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway ( nascent RNA-Seq )

PROVIDER: PRJNA994932 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25288864.fastq.gz	Fastqsanger.gz
	SRR25288865.fastq.gz	Fastqsanger.gz
	SRR25288866.fastq.gz	Fastqsanger.gz
	SRR25288867.fastq.gz	Fastqsanger.gz
	SRR25288868.fastq.gz	Fastqsanger.gz

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Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway ( nascent RNA-Seq )

Project description:Neuroinflammation is a common feature of neurodegenerative disorders such as Alzheimer's disease (AD). Neuroinflammation is induced by dysregulated glial activation, and astrocytes, the most abundant glial cells, become reactive upon neuroinflammatory cytokines released from microglia, and actively contribute to neuronal loss. Therefore, blocking reactive astrocyte functions is a viable strategy to manage neurodegenerative disorders. However, factors or therapeutics directly regulating astrocyte subtype remain unexplored. Here, we identified transcription factor NF-E2-related factor 2 (Nrf2) as a therapeutic target in neurotoxic reactive astrocytes upon neuroinflammation. We found that the absence of Nrf2 promoted the activation of reactive astrocytes in the brain tissue samples obtained from AD model 5xFAD mice, whereas enhanced Nrf2 expression blocked the induction of reactive astrocyte gene expression by counteracting NF-kB subunit p65 recruitment. Neuroinflammatory astrocytes robustly upregulated genes associated with type I interferon and the antigen-presenting pathway, which were suppressed by Nrf2 pathway activation. Moreover, impaired cognitive behaviors observed in AD mice were rescued upon ALGERNON2 treatment, which potentiated Nrf2 pathway and reduced the induction of neurotoxic reactive astrocytes. Thus, we highlight the potential of astrocyte-targeting therapy by promoting the Nrf2 pathway signaling for neuroinflammation-triggered neurodegeneration.

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Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway

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Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway (ChIP-Seq)

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Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway (ChIP-Seq)

Project description:Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway (ChIP-Seq)

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Project description:It is important to maintain cognitive integrity during underwater operations, which may also trigger cognitive alterations. Cognitive effect of underwater operations and the underlying mechanism remain elusive. Here, we found a single underwater operation affects cognition in a time-dependent model. Prolonged exposure elicits significant cognitive impairment and hippocampal dysfunction, which was accompanied by activation of microglia and upregulation of pro-inflammatory cytokines. RNA-sequencing supported the involvement of neuroinflammation and indicated the critical role of CCR3. Knockdown of CCR3 significantly rescued cognitive impairment and hippocampal dysfunction. Furthermore, the upregulation of pro-inflammatory cytokines was also reversed. Mechanistically, CCR3 knockdown switched the activated microglia from a pro-inflammatory to neuroprotective phenotype. Taken together, these results highlighted the time-dependent effects of a single underwater operation on cognitive function. Knocking down CCR3 can attenuate neuroinflammation by regulating polarization of activated microglia, thereby alleviating prolonged underwater operation-induced cognitive impairment.

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Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway

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