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Title: Investigating the impact of anaesthesia and surgery on Alzheimer's disease and the potential therapeutic role of Statin
Author: Lloyd, Dafydd
ISNI:       0000 0004 7228 3628
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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This study examines the impact of general anaesthesia, surgery and perioperative atorvastatin on Alzheimer's disease pathology in mice. A progressive neurodegenerative condition of complex aetiology, Alzheimer's is a common cause of dementia in humans but has no disease modifying treatment. Its long pre-symptomatic phase and lack of known biomarkers means asymptomatic individuals are exposed to modifiable risk factors in early life that influence disease progression and trajectory in the long term. Anaesthesia with surgery may be a modifiable risk factor. Neuroinflammation is a common feature of anaesthesia with surgery and Alzheimer's. Atorvastatin has potent anti-inflammatory pleiotropic effects that may be a useful perioperative intervention to modulate any acute on chronic neuroinflammatory interaction. The effects of the anaesthetic agents, isoflurane, nitrous oxide and xenon, were observed in immortal human cell lines that over-express APP and also in primary mouse hippocampal neurones incubated with amyloid beta. Altered distribution of APP, BACE-1 activity and differing expression of cleaved caspase-3 and BCL-2 were observed post exposure, with no change in gamma-secretase expression. The effects of anaesthesia, unilateral nephrectomy surgery and atorvastatin on pre-symptomatic and older APP23 mice (a murine model of Alzheimer's) were examined using behaviour techniques including Trace fear conditioning, Morris water maze and Y maze. Genotype dependent differences in learning were detected in different paradigms, as well as a post modifiable risk factor deficit in novel learning that was not seen after introduction of atorvastatin. Y maze performance showed changes in exploratory drive and working memory after the modifiable risk factor. Markers of neuroinflammation, synaptic function and amyloid beta pathology were quantified, showing a neuroinflammatory response and altered amyloid pathology, but no detectable change in synaptic marker after the modifiable risk factor. Anaesthesia with surgery does affect Alzheimer's neuropathology in mice, with perioperative atorvastatin changing both novel learning and working memory after anaesthesia with surgery.
Supervisor: Ma, Daqing ; Vizcaychipi, Marcela Sponsor: Alzheimer's Society ; National Institute for Health Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral