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Title: Investigating neurovascular function in pre-clinical models of Alzheimer's disease & atherosclerosis
Author: Shabir, Osman
ISNI:       0000 0004 9356 9342
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2020
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Background: Neurovascular coupling (NVC) is essential to brain health and the breakdown of NVC is proposed to be a key pathological factor in the development of Alzheimer’s disease (AD), vascular dementia (VaD) and other cerebrovascular diseases. Importantly; as we age, the presence of two or more comorbidities is common and this often leads to clinical complications. Whilst preclinical models of human disease are numerous and have supported basic and translational neuroscience immensely over the past few decades, models of comorbidity are few and often neglected when it is important to study comorbidity to reflect clinical presentations in patients. This project will focus on examining neurovascular function in 3 different preclinical models of AD, atherosclerosis (ATH) and comorbid AD & ATH (MIX). Aims & Objectives: I) To investigate neurovascular function at an early-AD timepoint (6m) in the J20-hAPP model of AD (J20-AD); when amyloid-beta deposits begin to form, using a chronic surgery recovered animal protocol. Neurovascular function will be assessed by 2D- optical imaging spectroscopy (2D-OIS) to measure cortical haemodynamics, in addition to using multichannel microelectrodes to obtain neural multi-unit activity (MUA). II) To investigate neurovascular function in a novel experimental model of ATH using the rAAV8-mPCSK9- D377Y + Western Diet model (PCSK9-ATH). III) To create a mixed comorbid model of AD and ATH (J20-PCSK9-MIX) and to investigate neurovascular function in this novel model. IV) To assess neuropathology and neuroinflammation from brain tissue in the 3 disease models. Results: Firstly, at an early stage, J20-AD mice exhibit enhanced evoked-haemodynamic responses associated with neural hyperexcitability. They also display a unique time- dependent elevation of baseline blood volume under normobaric hyperoxia. Secondly, PCSK9-ATH display reduced evoked-responses and show signs of neurovascular dysfunction associated with increased IL1β & TNFα-neuroinflammation. Thirdly, J20-PCSK9-MIX comorbid mice have a trebling of Aβ plaques in the hippocampus, although, without any further worsening of neurovascular function in the cortex compared to J20-AD mice, although all 3 disease models show a trend towards the reduced washout of HbR, which indicates metabolic inefficiency and inadequate oxygen delivery to neurons. Finally, electrode insertion into the brain (causing mild brain injury) leads to cortical spreading depression (CSD) to occur in all mice, with the most severe CSD occurring in J20-AD and PCSK9-ATH mice, and this may be related to levels of IL1β neuroinflammation, though this needs to be confirmed. Conclusions: These results provide novel insights in all 3 disease models which have important translational implications by highlighting distinct therapeutic targets and strategies. The results also show the importance of neurovascular function in dementia and targeting impairments to neurovascular function early on may be key to slowing down the onset and progression of dementia.
Supervisor: Berwick, Jason ; Francis, Sheila Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available