Mechanism underlying dysregulated cerebral vessel growth in Alzheimer’s disease
department or school: Medicine, Faculty of
department or school: Medical Genetics, Department of
data provider: DSpace
degree campus: UBCV
creator: Singh, Chaahat S. B.
issued: 2020-05-31T07:00:00Z
issued: 2019
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Alzheimer’s disease (AD), a neurodegenerative disorder of the elderly, causes loss of memory leading to dementia. The exact cause of this disease is still unknown, and the mechanism of pathogenesis highly debated. Amyloid beta (Aβ) peptide is central to the disease along with the cerebrovascular dysfunction and impaired cerebral blood flow (CBF). A strong link exitsts between brain vascular dysfunction and AD. This link was established due to evidence of reduced blood-brain barrier (BBB) integrity preceding various AD neuropathologies. Furthermore, BBB dysfunction could influence CBF, which in turn influences blood vessel growth. Current dogma holds that BBB leakiness is likely due to vascular deterioration. Inflammatory changes in the AD brain lead to up-regulation of mediators like, VEGF and Tie-2, that initiate angiogenesis. Studies indicate pathological angiogenesis and BBB disruption occur as a compensatory response to impaired CBF. Aβ-induced neuroinflammatory responses promote the generation of reactive oxygen species and further endothelial damage. Aβ is shown to be a modulator of blood vessel density and vascular remodeling via angiogenic mechanisms. Studies on the cerebrovascular integrity in AD model mice showed a significant increase in the incidence of disrupted tight junctions which is directly linked to an increase in microvascular density. This strongly supports amyloidgenesis-triggered angiogenesis as the basis of BBB disruption. This thesis aims in attempting to curb vascular damage seen in the brains of AD mice and improve cognition by treating them with anti-angiogenic drugs providing scope for these to modulate cerebral angiogenesis to ameliorate Aβ load, reduce vasculature damage and reverting cognitive decline. This may facilitate new preventive and therapeutic interventions for not only AD but also related vascular diseases such as small vessel disease. As a part of the study, a mechanism for vascular dysfunction in AD is proposed as follows:…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/70005
note: MECHANISM UNDERLYING DYSREGULATED CEREBRAL VESSEL GROWTH IN ALZHEIMER’S DISEASE by Chaahat S.B. Singh B.Sc., Guru Nanak Dev University, 2008 M.Sc. (Hons.), Guru Nanak Dev University, 2010 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Doctor of Philosophy in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2019 © Chaahat S.B. Singh, 2019 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: MECHANISM UNDERLYING DYSREGULATED CEREBRAL VESSEL GROWTH IN ALZHEIMER’S DISEASE submitted by Chaahat S.B. Singh in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Genetics Examining Committee: Dr. Wilfred A. Jefferies Supervisor Dr. Jan Friedman Supervisory Committee Member Dr. Peter Soja Supervisory Committee Member Dr. Haakon Nygaard University Examiner Dr. Stanley Floresco University Examiner Additional Supervisory Committee Members: Dr. Wolfram Tetzlaff Supervisory Committee Member iii Abstract Alzheimer’s disease (AD), a neurodegenerative disorder of the elderly, causes loss of memory leading to dementia. The exact cause of this disease is still unknown, and the mechanism of pathogenesis highly debated. Amyloid beta (Aβ) peptide is central to the disease along with the cerebrovascular dysfunction and impaired cerebral blood flow (CBF). A strong link exitsts between brain vascular dysfunction and AD. This link was established due to evidence of reduced blood-brain barrier (BBB) integrity preceding various AD neuropathologies. Furthermore, BBB dysfunction could influence CBF, which in turn influences blood vessel growth. Current dogma holds that BBB leakiness is likely due to vascular deterioration. Inflammatory changes in the AD brain lead to up-regulation of mediators like, VEGF and Tie-2, that initiate angiogenesis. St…
has type: Thesis/Dissertation
date issued: 2019-05
is shown at: 10.14288/1.0378519
language: eng
degree discipline: Medical Genetics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/70005