Aliev Gjumrakch, Smith Mark A, Obrenovich Mark E, de la Torre Jack C, Perry George
The Microscopy Research Center and Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland OH 44106, USA.
Neurotox Res. 2003;5(7):491-504. doi: 10.1007/BF03033159.
Chronic vascular hypoperfusion induces oxidative stress and brain energy failure, and leads to neuronal death, which manifests as cognitive impairment and the development of brain pathology as in Alzheimer disease (AD). It is becoming more widely accepted that AD is characterized by impairments in energy metabolism. We hypothesize that hypoperfusion-induced mitochondrial failure plays a central role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and neuronal cell bodies in AD. All of these changes have been found to occur before pathology and coexist during the progression of AD. In this review we have summarized recent evidence and our own knowledge regarding the relationship between the hypoperfusion-induced vascular damage that initiates oxidative stress and mitochondrial abnormalities that appear to be a key target for the development of AD pathology. Future investigations into both the mechanisms behind amyloid beta (Abeta) deposition and the possible accelerating effects of environmental factors, such as chronic hypoxia/reperfusion may open the door for effective pharmacological treatments of AD. We hypothesize that an imbalance between endothelium derived vasoconstrictors and vasodilators, along with an antioxidant system deficiency and mitochondria lesions are prominent in AD. Future studies examining the importance of mitochondrial pathophysiology in different brain cellular compartments may provide insight not only into neurodegenerative and/or cerebrovascular disease pathobiology but may also provide targets for treating these conditions.
慢性血管灌注不足会引发氧化应激和脑能量衰竭，进而导致神经元死亡，表现为认知障碍以及如阿尔茨海默病（AD）中出现的脑部病理改变。越来越多人接受AD的特征是能量代谢受损这一观点。我们推测，灌注不足诱导的线粒体功能衰竭在活性氧的产生中起核心作用，导致对脑内细胞区室的氧化损伤，尤其是在AD患者的血管内皮和神经元细胞体中。所有这些变化都被发现发生在病理改变之前，并在AD进展过程中共存。在这篇综述中，我们总结了近期的证据以及我们自己关于灌注不足诱导的血管损伤引发氧化应激与线粒体异常之间关系的认识（线粒体异常似乎是AD病理发展的关键靶点）。未来对淀粉样β蛋白（Aβ）沉积背后机制以及环境因素（如慢性缺氧/再灌注）可能的加速作用的研究，或许会为AD的有效药物治疗打开大门。我们推测，内皮源性血管收缩剂和血管舒张剂之间的失衡，以及抗氧化系统缺陷和线粒体损伤在AD中较为突出。未来研究不同脑内细胞区室中线粒体病理生理学的重要性，不仅可能为神经退行性和/或脑血管疾病的病理生物学提供见解，还可能为治疗这些疾病提供靶点。
