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Title: The role of capillary pericytes in cerebral blood flow changes during ischaemia and in Alzheimer's disease
Author: Nortley, Ross R.
ISNI:       0000 0004 7660 1929
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Recently, it was found that brain capillary pericytes play a significant role in controlling cerebral blood flow. Pericytes may therefore also play an important pathological role when cerebral blood flow is compromised, both acutely, as occurs during ischaemic stroke, and chronically, as occurs in Alzheimer's disease. In this thesis I have investigated the role of brain capillary pericytes as follows. (1) Ischaemia: Pericytes have been suggested to constrict capillaries and subsequently die in rigor during ischaemia, making them a therapeutic target after acute stroke when a long-lasting decrease of cerebral blood flow occurs despite re-opening of the occluded artery. I confirmed that pericytes constrict and die in rigor during ischaemia and demonstrated that the L-type Ca2+ channel blocker nimodipine inhibits ischaemia-induced pericyte constriction. (2) Alzheimer's disease (AD): Vascular compromise occurs early in AD and amyloid β (Aβ) has been shown to reduce cerebral blood flow. In the cerebral vasculature most resistance is in capillaries, so Aβ might primarily act on contractile capillary pericytes. I used live and fixed human tissue to establish disease-relevance, and rodent experiments to define mechanism, to show that Aβ constricts brain capillaries at pericyte locations. Applying soluble Aβ oligomers to live human cortical tissue constricted capillaries by 25%. Using rat cortical slices this was shown to reflect Aβ evoking capillary pericyte contraction, with an EC50 of 4.7 nM, by generating reactive oxygen species and activating endothelin ET-A receptors. In freshly-fixed diagnostic biopsies from human patients investigated for cognitive decline, mean capillary diameters were 8.1% less in patients showing Aβ deposition than in patients without Aβ deposition. For patients with Aβ deposition, capillary diameter was 31% less at pericyte somata than away from the somata, predicting a halving of blood flow. Constriction of capillaries by Aβ will contribute to the cerebral energy deficit occurring in AD, which promotes further Aβ generation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available