Centre for Computational Imaging and Simulation Technologies in Biomedicine (CISTIB), Department of Electronic and Electrical Engineering, University of Sheffield, Sheffield, UK.
Department of Neuroscience, Medical School, University of Sheffield, Sheffield, UK; IRCCS San Camillo Foundation Hospital, Venice, Italy.
Neurobiol Dis. 2015 Oct;82:593-606. doi: 10.1016/j.nbd.2015.08.014. Epub 2015 Aug 23.
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.
迟发性痴呆是老龄化人口的主要健康问题。阿尔茨海默病（AD）占老年人群中痴呆病例的最大比例（65-70%）。尽管进行了大量研究，但迟发性 AD 的发病机制仍不清楚。大量证据表明，神经退行性过程是由衰老和心血管疾病引起的慢性脑灌注不足（CCH）引发的。CCH 导致大脑的氧气、葡萄糖和其他营养供应减少，不仅直接损害实质细胞，还损害血脑屏障（BBB），后者是大脑内环境稳定的关键介质。BBB 功能障碍通过促进氧化应激、炎症、细胞旁通透性和一氧化氮（一种区域血流的关键调节剂）失调，介导 CCH 的间接神经毒性作用。因此，BBB 功能障碍介导了一个恶性循环，即脑灌注进一步减少，神经退行性过程加速。内皮细胞与周细胞和星形胶质细胞的相互作用也可能在这个过程中发挥作用。血管功能障碍和神经退行性变之间的相互作用可能进一步导致疾病的发展。目前缺乏对相互作用的内皮介导过程的复杂情况的全面概述，这可能有助于确定适当的治疗干预措施。本研究综述了 AD 发病机制中内皮介导的血管功能障碍的体外和离体研究的当前文献，旨在全面概述因果关系的复杂网络。特别强调了可以加速神经血管退化过程的恶性循环。
