Vascular dysfunction in the pathogenesis of Alzheimer's disease - A review of endothelium-mediated mechanisms and ensuing vicious circles

Luigi Yuri Di Marco, Annalena Venneri, E. Farkas, Paul C. Evans, Alberto Marzo, Alejandro F. Frangi

Research output: Contribution to journalArticle

98 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)593-606
Number of pages14
JournalNeurobiology of Disease
Volume82
DOIs
Publication statusPublished - Feb 28 2015

Fingerprint

Blood-Brain Barrier
Endothelium
Blood Vessels
Alzheimer Disease
Dementia
Pericytes
Regional Blood Flow
Astrocytes
Population
Permeability
Nitric Oxide
Oxidative Stress
Homeostasis
Perfusion
Oxygen
Inflammation
Glucose
Food
Health
Brain

Keywords

  • Alzheimer's disease
  • Blood-brain barrier permeability
  • Cerebral hypoperfusion
  • Endothelial dysfunction
  • Mitochondrial dysfunction
  • Ultrastructural damage

ASJC Scopus subject areas

  • Neurology

Cite this

Vascular dysfunction in the pathogenesis of Alzheimer's disease - A review of endothelium-mediated mechanisms and ensuing vicious circles. / Di Marco, Luigi Yuri; Venneri, Annalena; Farkas, E.; Evans, Paul C.; Marzo, Alberto; Frangi, Alejandro F.

In: Neurobiology of Disease, Vol. 82, 28.02.2015, p. 593-606.

Research output: Contribution to journalArticle

Di Marco, Luigi Yuri ; Venneri, Annalena ; Farkas, E. ; Evans, Paul C. ; Marzo, Alberto ; Frangi, Alejandro F. / Vascular dysfunction in the pathogenesis of Alzheimer's disease - A review of endothelium-mediated mechanisms and ensuing vicious circles. In: Neurobiology of Disease. 2015 ; Vol. 82. pp. 593-606.
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