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

• Published in: Neurobiology of disease Vol. 82; pp. 593 - 606
• Main Authors: Di Marco, Luigi Yuri, Venneri, Annalena, Farkas, Eszter, Evans, Paul C, Marzo, Alberto, Frangi, Alejandro F
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2015; Elsevier
• Subjects: Alzheimer Disease - physiopathology; Alzheimer's disease; Animals; Blood-Brain Barrier - physiopathology; Blood–brain barrier permeability; Cerebral hypoperfusion; Cerebrovascular Circulation - physiology; Endothelial dysfunction; Endothelium, Vascular - physiopathology; Humans; Mitochondrial dysfunction; Neurology; Ultrastructural damage; Glucose transporter 1; eNOS; Protein kinase C; BBB; Tumour necrosis factor-α; NF-kB; HIF-1α; ICAM-1; Mesenchyme homeobox gene-2; Mitochondrial DNA; Cerebrospinal fluid; Low-density lipoprotein receptor-related protein 1; Aβ; IFN-γ; Interferon-γ; BACE-1; GLUT-1; RNS; UPR; Endothelial dysfunction; iNOS; mitoK ATP; Alzheimer's disease; NFT; Vascular endothelial growth factor; Aβ precursor protein; AQP; Monocyte chemoattractant protein-1; Hypoxia-inducible factor 1α; AD; IL; P-gp; PKC; Endothelin 1; Neurofibrillary tangle; Receptor for advanced glycation end-products; ER; Ultrastructural damage; Nuclear factor kappa B; MEOX-2; ET-1; Nitric oxide; Transforming growth factor-β; Intercellular adhesion molecule-1; ROS; Platelet endothelial cell adhesion molecule 1; Tight junction; Endoplasmic reticulum; Aquaporin; NO; PECAM-1; ABC; Inositol 1,4,5-triphosphate; MCP-1; Reactive oxygen species; mtDNA; CBF; Interleukin; Reactive nitrogen species; Blood–brain barrier; Unfolded protein response; Trans-endothelial electrical resistance; β-site AβPP cleaving enzyme 1; Apolipoprotein E; Cerebral blood flow; Inducible nitric oxide synthase; CSF; IP 3; TGF-β; ApoE; Amyloid-β; Blood–brain barrier permeability; Mitochondrial dysfunction; VEGF; Cerebral hypoperfusion; RAGE; ATP binding cassette; P-glycoprotein; Endothelial nitric oxide synthase; TNF-α; ATP-sensitive potassium channels; TJ; TEER; AβPP; LRP-1; Positron emission tomography; PET; mitoKATP; IP3
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2015.08.014

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.