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Astrocyte-specific overexpression of Nrf2 protects against optic tract damage and behavioural alterations in a mouse model of cerebral hypoperfusion

Sigfridsson, Emma, Marangoni, Martina, Johnson, Jeffrey A., Hardingham, Giles E., Fowler, Jill H., Horsburgh, Karen·2018·Scientific Reports
DOI 10.1038/s41598-018-30675-4PMC PMC6105641
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Abstract

Mouse models have shown that cerebral hypoperfusion causes white matter disruption and memory impairment relevant to the study of vascular cognitive impairment and dementia. The associated mechanisms include inflammation and oxidative stress are proposed to drive disruption of myelinated axons within hypoperfused white matter. The aim of this study was to determine if increased endogenous anti-oxidant and anti-inflammatory signalling in astrocytes was protective in a model of mild cerebral hypoperfusion. Transgenically altered mice overexpressing the transcription factor Nrf2 (GFAP-Nrf2) and wild type littermates were subjected to bilateral carotid artery stenosis or sham surgery. Behavioural alterations were assessed using the radial arm maze and tissue was collected for pathology and transcriptome analysis six weeks post-surgery. GFAP-Nrf2 mice showed less pronounced behavioural impairments compared to wild types following hypoperfusion, paralleled by reduced optic tract white matter disruption and astrogliosis. There was no effect of hypoperfusion on anti-oxidant gene alterations albeit the levels were increased in GFAP-Nrf2 mice. Instead, pro-inflammatory gene expression was determined to be significantly upregulated in the optic tract of hypoperfused wild type mice but differentially affected in GFAP-Nrf2 mice. In particular, complement components (C4 and C1q) were increased in wild type hypoperfused mice but expressed at levels similar to controls in hypoperfused GFAP-Nrf2 mice. This study provides evidence that overexpression of Nrf2 in astrocytes exerts beneficial effects through repression of inflammation and supports the potential use of Nrf2-activators in the amelioration of cerebrovascular-related inflammation and white matter degeneration.

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  • The temporal pattern of NRF2 and SOD reflects activation of the Nrf2-ARE axis, which promotes transcription of antioxidant enzymes and restores redox balance.

    “We propose that this temporal pattern reflects activation of the nuclear factor erythroid 2‐related factor 2‐antioxidant response element (Nrf2‐ARE) axis, which promotes the transcription of antioxidant enzymes and restores redox balance (Sigfridsson et al. 2018; He and Hewett 2025).”

    From LDL Cholesterol Modulates Astrocyte Metabolism, Lipid Handling, and Morphology: Evidence From In Vitro and In Vivo Models (2026) · cites this paper as Sigfridsson et al. 2018

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Metadata

Authors
Sigfridsson, E., Marangoni, M., Johnson, J. A., Hardingham, G. E., Fowler, J. H., & Horsburgh, K.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-08-22
Volume
8
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-018-30675-4
PMC
PMC6105641
Cited by
41
References
12
Language
en
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