title: Vascular dysfunction in the pathogenesis of Alzheimer's disease--A review of endothelium-mediated mechanisms and ensuing vicious circles.
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.
authors: Centre for Computational Imaging and Simulation Technologies in Biomedicine (CISTIB), Department of Electronic and Electrical Engineering, University of Sheffield, Sheffield, UK. Electronic address: luigiyuri.dimarco@gmail.com.
authors: Luigi Yuri
authors: LY
authors: Di Marco
authors: Department of Neuroscience, Medical School, University of Sheffield, Sheffield, UK; IRCCS San Camillo Foundation Hospital, Venice, Italy.
authors: Annalena
authors: A
authors: Venneri
authors: Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
authors: Eszter
authors: E
authors: Farkas
authors: Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield, UK.
authors: Paul C
authors: PC
authors: Evans
authors: Centre for Computational Imaging and Simulation Technologies in Biomedicine (CISTIB), Department of Mechanical Engineering, University of Sheffield, Sheffield, UK.
authors: Alberto
authors: A
authors: Marzo
authors: Centre for Computational Imaging and Simulation Technologies in Biomedicine (CISTIB), Department of Electronic and Electrical Engineering, University of Sheffield, Sheffield, UK.
authors: Alejandro F
authors: AF
authors: Frangi
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006801:Humans
keywords: Alzheimer's disease; Blood–brain barrier permeability; Cerebral hypoperfusion; Endothelial dysfunction; Mitochondrial dysfunction; Ultrastructural damage