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.
Highlights
Vascular cognitive impairment (VCI) is a spectrum of mild cognitive impairment to vascular dementia and is influenced by risk factors including age, hypertension and atherosclerosis
Cortical cerebral blood flow (CBF) was evaluated user laser speckle imaging at baseline and at 24 hours and 6 weeks after surgery to assess the temporal response to carotid artery stenosis and to determine if there was a difference between wild type and Glial fibrillary acidic protein (GFAP)-Nrf[2] mice (Fig. 1)
Post hoc analysis indicated that CBF was significantly reduced in wild type and GFAP-Nrf[2] hypoperfused mice from their corresponding sham controls at 24 hours (p < 0.001) and 6 weeks (WT; p < 0.001, GFAPNrf[2]; p = 0.03)
Summary
Vascular cognitive impairment (VCI) is a spectrum of mild cognitive impairment to vascular dementia and is influenced by risk factors including age, hypertension and atherosclerosis. There appears to be a close link between damage to white matter, microgliosis and white matter function in response to mild[17] and severe cerebral hypoperfusion[18]. We have shown that treatment with DMF, in a severe model of cerebral hypoperfusion, ameliorates white matter functional impairment and microgliosis[18]. Since astrocyte specific overexpression of Nrf[2] has been shown to confer white matter protection in a number of disease models, we wished to build on this work to interrogate the effects of increased expression of astrocytic Nrf[2] on white matter vulnerability and behavioural outcomes which are impaired in response to cerebral hypoperfusion. We hypothesised that overexpression of astrocytic Nrf[2] would alleviate hypoperfusion induced cognitive impairment by reducing white matter disruption and inflammation, through glutathione-related mechanisms
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