Endothelin-1 mediated vasoconstriction and cerebral hypoperfusion in Alzheimer’s disease

Abstract

Cerebral hypoperfusion, associated with cognitive decline, is a hallmark of vascular dementia and is now recognised to be a key pathological feature in the early stages of Alzheimer’s disease (AD). This thesis aims to explore the hypothesis that pericyte-mediated contraction, as a result of elevated endothelin-1 (EDN1; a potent vasoconstrictor), is a major contributor to cerebral hypoperfusion in AD. Electrical impedance assays (xCELLigence) have been used to characterise and then explore the impact of amyloid-beta (Aβ) peptides on EDN1-mediated contraction of human brain-derived vascular pericytes in vitro. The expression of endothelin receptors type-A (EDNRA) and type-B (EDNRB) have been characterised in cultured pericytes after 1- and 24-hour Aβ exposure and in human post-mortem brain tissue in AD. The major findings indicate that human brain-derived vascular pericytes contract in response to EDN1 acting via EDNRA; adult brain-derived pericytes are less responsive than foetal pericytes to EDN1; EDN1-mediated pericyte contraction is dysregulated in the presence of physiological concentrations of Aβ peptides and that exposure to Aβ induces the gene and protein expression of EDNRA (or increased ratio of EDNRA:EDNRB). In human brain tissue, EDNRA level (but not gene expression) is upregulated in AD and was associated with Aβ plaque load. The findings presented in this thesis support the hypothesis that increased pericyte contraction (because of elevated EDN1), and dysregulated pericyte contraction (because of increased Aβ), contribute to the impairment of neurovascular coupling in AD. In conclusion, abnormal EDN1-evoked pericyte contraction is likely to be a major contributor to capillary vasoconstriction and thus cerebral hypoperfusion in AD.

Date of Award	9 May 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	J S Miners (Supervisor) & Seth Love (Supervisor)