Protective effects of astrocyte-specific upregulation of Nrf2 in a mouse model of Vascular Cognitive Impairment

1) University of Edinburgh, Centre for Neuroregeneration, 2) University of Edinburgh, Centre for Integrative Physiology

A prominent feature of vascular cognitive impairment is chronic cerebral hypoperfusion, where extent of regional cerebral blood flow (CBF) reductions is a predictor of mild cognitive impairment progression to dementia. We have previously demonstrated that oxidative stress and pro-inflammatory mechanisms may contribute to cognitive decline in a mouse model of  chronic hypoperfusion. Nrf2 is a transcription factor regulating a plethora of antioxidant and anti-inflammatory genes which has been implicated in several disease models of neurodegeneration. We hypothesised that overexpression of Nrf2 in astrocytes would attenuate hypoperfusion-induced impairment in spatial working memory via anti-inflammatory/oxidative stress mechanisms. Transgenic mice overexpressing Nrf2 in astrocytes (GFAP-Nrf2; 4fold increase relative to wild type mice) and WT littermates underwent hypoperfusion surgery induced by permanent bilateral carotid artery stenosis using microcoils, and were compared to sham controls (WT n=16, GFAP-Nrf2 n=20). Resting cortical CBF was measured temporally using laser speckle imaging and spatial working memory was assessed using the radial arm maze 1 month after surgery. Brains were collected for pathology and biochemistry 6 weeks after surgery. Chronic cerebral hypoperfusion induced a pronounced impairment in spatial working memory in WT mice, however, the magnitude of impairment was significantly less in the GFAP-Nrf2 group (*p<0.05). There was evidence of microgliosis following hypoperfusion, which in some regions appeared less pronounced in GFAP-Nrf2 mice (not significant). Cortical CBF was significantly reduced at 24 hours and 6 weeks with carotid stenosis compared to shams in both groups but there was no genotype effect. It was noted though that at 6 weeks the magnitude of CBF reduction was less in GFAP-Nrf2 relative to WT. Overexpression of Nrf2 exerts protective effects on cognition in a model of vascular cognitive impairment, with evidence of reduced neuroinflammation and blood flow. Current studies are investigating mechanisms that may be involved.

Funded by: The Alzheimer's Society

* entered into the PhD student poster competition