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The effect of cholinergic loss on the structure and function of the neurovascular unit: implications for cerebral amyloid angiopathy

Nizari, Shereen (2019). The effect of cholinergic loss on the structure and function of the neurovascular unit: implications for cerebral amyloid angiopathy. PhD thesis The Open University.

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Abstract

Innervation of cerebral blood vessels is important for the regulation of vascular tone and adequate cerebral perfusion. Alzheimer’s disease (AD) is characterised by a loss of cholinergic innervation of the neurovascular unit (NVU). This loss may contribute not only to inefficient cerebrovascular perfusion, but also to the failure of removal of amyloid-β (Aβ), leading to its accumulation as cerebral amyloid angiopathy (CAA). This hypothesis was tested by mimicking loss of cholinergic innervation of the cortex and hippocampus in adult male C57BL/6 mice using the immunospecific toxin mu-p75-saporin. Using quadruple labelling immunohistochemistry and 3D reconstructions of the NVU, loss of perivascular cholinergic innervation was observed at the smooth muscle cells and basement membrane in the cortex and hippocampus, with additional perivascular loss at the astrocyte endfeet in the cortex. Arterial spin labelling fMRI revealed no differences in resting cerebral blood flow between control and saporin-treated mice in either the cortex or hippocampus. However, denervated vessels in the cortex, but not the hippocampus, failed to respond to pharmacological stimulation of endothelial nitric oxide synthase (eNOS). Further studies revealed a decrease in eNOS expression in the cortex, but an increase in eNOS expression and activity in the hippocampus following loss of cholinergic input. No differences were noted between control and saporin-treated mice in the efficiency of removal of Aβ along perivascular basement membranes in either the cortex or hippocampus. Treatment of TetO-APPSweInd mice with saporin resulted in a trend towards higher CAA load. These data suggest that there are innate differences between NVUs of the cortex and the hippocampus and a difference in their functional response to loss of cholinergic input. Loss of cholinergic input at the NVU may contribute to accumulation of Aβ; however, this likely requires additional pathological factors for CAA to develop.

Item Type: Thesis (PhD)
Copyright Holders: 2018 The Author
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM)
Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Item ID: 60909
Depositing User: Shereen Nizari
Date Deposited: 03 Jun 2019 13:25
Last Modified: 05 Oct 2019 09:42
URI: http://oro.open.ac.uk/id/eprint/60909
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