Aliyev Ali, Chen Shu G, Seyidova Dilara, Smith Mark A, Perry George, de la Torre Jack, Aliev Gjumrakch
The Microscopy Research Center, Case Western Reserve University, Cleveland, OH 44106, USA.
J Neurol Sci. 2005 Mar 15;229-230:285-92. doi: 10.1016/j.jns.2004.11.040. Epub 2004 Dec 23.
The pathogenesis, which is primarily responsible for Alzheimer's disease (AD) and cerebrovascular accidents (CVA), seems to involve chronic hypoperfusion. The role of hypoperfusion, as a key factor for vascular lesions that causes oxidative stress, appears to be widely accepted as an initiator of AD. Specifically, accumulated oxidative stress increases vascular endothelial permeability and promotes leukocyte adhesions, which is coupled with alterations in endothelial signal transduction and redox-regulated transcription factors. Based on these recent findings, we hypothesize that the cellular and molecular mechanisms by which hypoperfusion-induced reactive oxygen species (ROS) accumulation impairs endothelial barrier function and promotes leukocyte adhesion induces alterations in normal vascular function and results in the development of AD. We are theorizing that mitochondria play a key role in the generation of ROS, resulting in oxidative damage to neuronal cell bodies, as well as other cellular compartment in the AD brain. All of these changes have been found to accompany AD pathology. We have studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD, yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (AbetaPP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild and 5 kb deleted types and mouse types was performed along with immunocytochemistry using antibodies against amyloid precursor protein (APP), 8-hydroxy-2'-guanosine (8-OHG) and cytochrome c oxidase (COX). There was a higher degree of amyloid deposition, overexpression of oxidative stress markers, mitochondria DNA deletion and mitochondrial structural abnormality in the vascular walls of the human AD, YAC and C57B6/SJL Tg (+) mice compared to age-matched controls. Therefore, selective pharmacological intervention, directed for abolishing the chronic hypoperfusion state, would possibly change the natural course of development of dementing neurodegeneration.
主要导致阿尔茨海默病（AD）和脑血管意外（CVA）的发病机制似乎涉及慢性灌注不足。灌注不足作为导致氧化应激的血管病变的关键因素，其作用似乎已被广泛认为是AD的引发因素。具体而言，累积的氧化应激会增加血管内皮通透性并促进白细胞黏附，这与内皮信号转导和氧化还原调节转录因子的改变相关。基于这些最新发现，我们推测灌注不足诱导的活性氧（ROS）积累损害内皮屏障功能并促进白细胞黏附的细胞和分子机制会导致正常血管功能改变并引发AD的发展。我们推测线粒体在ROS的产生中起关键作用，导致对神经元细胞体以及AD大脑中的其他细胞区室的氧化损伤。所有这些变化都已被发现与AD病理学相伴。我们研究了来自人类AD、酵母人工染色体（YAC）和过表达淀粉样β前体蛋白（AβPP）的C57B6/SJL转基因阳性（Tg+）小鼠的脑血管壁细胞中血管病变和线粒体的超微结构特征。使用针对人类野生型和5 kb缺失型以及小鼠型的线粒体DNA（mtDNA）探针进行原位杂交，并使用针对淀粉样前体蛋白（APP）、8-羟基-2'-鸟苷（8-OHG）和细胞色素c氧化酶（COX）的抗体进行免疫细胞化学。与年龄匹配的对照相比，人类AD、YAC和C57B6/SJL Tg（+）小鼠的血管壁中淀粉样沉积程度更高、氧化应激标志物过表达、线粒体DNA缺失和线粒体结构异常。因此，旨在消除慢性灌注不足状态的选择性药物干预可能会改变痴呆性神经退行性变的自然发展进程。
