Di Marco, L.Y., Venneri, A., Farkas, E. et al. (3 more authors) (2015) Vascular dysfunction in the pathogenesis of Alzheimer's disease - A review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiology of Disease, 82. 593 - 606. ISSN 0969-9961
Abstract
Late-onset dementia is a major health concern in the ageing population. Alzheimer's disease (AD) accounts for the largest proportion (65-70%) of dementia cases in the older population. Despite considerable research effort, the pathogenesis of late-onset AD remains unclear. Substantial evidence suggests that the neurodegenerative process is initiated by chronic cerebral hypoperfusion (CCH) caused by ageing and cardiovascular conditions. CCH causes reduced oxygen, glucose and other nutrient supply to the brain, with direct damage not only to the parenchymal cells, but also to the blood-brain barrier (BBB), a key mediator of cerebral homeostasis. BBB dysfunction mediates the indirect neurotoxic effects of CCH by promoting oxidative stress, inflammation, paracellular permeability, and dysregulation of nitric oxide, a key regulator of regional blood flow. As such, BBB dysfunction mediates a vicious circle in which cerebral perfusion is reduced further and the neurodegenerative process is accelerated. Endothelial interaction with pericytes and astrocytes could also play a role in the process. Reciprocal interactions between vascular dysfunction and neurodegeneration could further contribute to the development of the disease.A comprehensive overview of the complex scenario of interacting endothelium-mediated processes is currently lacking, and could prospectively contribute to the identification of adequate therapeutic interventions. This study reviews the current literature of in vitro and ex vivo studies on endothelium-mediated mechanisms underlying vascular dysfunction in AD pathogenesis, with the aim of presenting a comprehensive overview of the complex network of causative relationships. Particular emphasis is given to vicious circles which can accelerate the process of neurovascular degeneration.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2015 Published by Elsevier Inc. This is an author produced version of a paper subsequently published in Neurobiology of Disease. Uploaded in accordance with the publisher's self-archiving policy. Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
Keywords: | Alzheimer's disease; Blood–brain barrier permeability; Cerebral hypoperfusion; Endothelial dysfunction; Mitochondrial dysfunction; Ultrastructural damage |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Engineering (Sheffield) > Department of Mechanical Engineering (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 26 Jan 2016 14:01 |
Last Modified: | 01 Nov 2016 22:01 |
Published Version: | http://dx.doi.org/10.1016/j.nbd.2015.08.014 |
Status: | Published |
Publisher: | Elsevier |
Refereed: | Yes |
Identification Number: | 10.1016/j.nbd.2015.08.014 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:92486 |