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Title: Characterisation of Nrf2-signalling and the effects of boosting astrocytic Nrf2 in a mouse model of ischaemic stroke
Author: Aimable, Margaux
ISNI:       0000 0004 8509 2636
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2020
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Stroke is the leading cause of disability for adults and the second leading cause of death worldwide. It is characterised by a sudden weakness or numbness of the face, arm or leg, most often on one side of the body. The most common type of stroke is an ischaemic stroke, the blockage of a cerebral vessel and is causing dementia. Nuclear Factor Erythroid 2 (NFE2)- Related Factor 2 (Nrf2) is a transcription factor and master regulator of a battery of antioxidant and anti-inflammatory genes such as Heme oxygenase-1 (hmox1), NAD(P)H dehydrogenase quinone 1 (nqo1), glutamate-cystine antiporter (xCT; gene slc7a11), sulfiredoxin 1 (srxn1). As astrocytes play a central role in the neuroprotective effects of boosting Nrf2, the overarching hypothesis of the present work is that boosting the Nrf2 pathway in astrocytes will prevent oxidative stress and pro-inflammatory damage caused by ischaemia/reperfusion and thereby protect neurons from damage and diminish cognitive deficits and neurodegeneration that may lead to dementia. A mouse model of transient focal cerebral ischaemia was chosen to reproduce ischaemia in controlled conditions, by occluding the middle cerebral artery. Modest duration of ischaemia (15 minutes) was sufficient to cause ischaemic neuronal damage in the striatum and to significantly increase oxidative stress, inflammatory markers and to activate Nrf2-signalling. Furthermore, oxidative stress and inflammation were found despite reperfusion and in areas spared of neuronal death, suggesting they may still be at risk of cellular damage. Despite persistent elevations in oxidative stress, inflammatory glial cells and cytokines 4 weeks after ischaemia, there were no alterations to Nrf2-signalling suggesting that boosting Nrf2- signalling may confer protective effects. Nrf2 overexpression in GFAP-expressing astrocytes in a mouse model (GFAP-Nrf2 mice) has been shown to confer protection against inflammation and oxidative stress in neurodegenerative models. Following ischaemia, GFAP-Nrf2 mice presented a significant reduction of neuronal damage, oxidative stress was markedly reduced, and levels of reactive astrocytes were increased in the peri-infarct of the cortex. This was paralleled with a significant increase of cxcl10 and anti-inflammatory il-4rα cytokine gene expression. These promising results led to next study the potential protective effects of boosting Nrf2 in astrocytes on cognitive and neurological deficits 4 weeks after ischaemic stroke. In this experiment, ischaemia impaired cognitive functions at 4 weeks and this was paralleled with oxidative stress and inflammation. Neuronal damage caused by ischaemia was not significantly altered between wild-type and GFAP-Nrf2 animals despite upregulated Nrf2- signalling in GFAP-Nrf2 mice compared to wild-types. Nrf2 overexpression in astrocytes increased microglial response and reduced inflammatory c3, but their cognitive functions were further impaired compared to wild-types. Altogether these studies suggest that Nrf2 exerts different effects after ischaemia depending on the severity of stroke and the timepoint analysed. Furthermore, these results suggest that there is ongoing signalling between microglia and astrocytes. This work provides an original contribution to understanding the potential protective effects of Nrf2 overexpression in astrocytes and its limitations.
Supervisor: Fowler, Jill ; Spires-Jones, Tara ; Yau, Joyce Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: stroke ; cerebral ischaemia ; oxidative stress ; Nrf2 ; astrocytes ; Nrf2-signalling ; mouse model