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Title: Nrf2 in metabolic related inflammation in the brain
Author: Liddell, Mary Katherine
ISNI:       0000 0004 5371 1930
Awarding Body: University of Dundee
Current Institution: University of Dundee
Date of Award: 2015
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Novel approaches are required to address Alzheimer’s disease (AD) in our ageing population, with recent interest focused on inflammation and oxidative stress (OS). Disruption of NF-E2-related factor 2 (Nrf2) signalling increases OS and promotes AD. Amyloid precursor protein (APP) is intimately linked with AD, with the Swedish mutation (hAPPswe) used in numerous transgenic models. Furthermore, increasing importance has been placed on the suggested link between nutritional status and AD. To assess Nrf2 as a potential target in AD, we examined the effect of metabolic stress, by chronic high fat (HF) feeding or acute lipopolysaccharide (LPS) treatment on the brains of aged WT, Nrf2-/-, hAPPswe and Nrf2-/-/hAPPswe mice.  Nrf2-/- mice displayed impaired enthorinal cortex-dependent cognition, with raised basal hippocampal inflammation. The inflammatory state was attenuated by chronic HF feeding, whilst maintaining insulin sensitivity. In contrast, hAPPswe did not display an inflammatory response to HF feeding, but demonstrated impaired insulin signalling; in line with AD-associated insulin resistance. Additionally, Nrf2-/- mice display increased glial cell activation and activation of mitogen activated protein kinases and mitochondrial impairment. These may be indicative of OS-induced cellular dysfunction and is supported by an aggravated response to LPS, which potentiates IL-1β production. Furthermore, despite an attenuated LPS response following the induction of tolerance, Nrf2-/- mice maintain glial cell activation following treatment which may be suggestive of a primed immune environment within the brain.  In conclusion, these data indicate altered glucose homeostasis in both Nrf2-/- and hAPPswe mice, as previously reported. Further, we advocate that Nrf2 plays a key role in mitochondrial function and health and may be important for the ameliorative effects of HF feeding. Taken together, mitochondrial dysregulation and associated OS may help explain the development of cognitive impairment in Nrf2-/- mice. This may be relevant for AD given the age-dependent decline in Nrf2 expression in humans.
Supervisor: Ashford, Michael Sponsor: Alzheimer's Society ; Alzheimer's Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Nrf2 ; Alzheimer's disease ; Obesity ; APP