Ferreiro E, Baldeiras I, Ferreira I L, Costa R O, Rego A C, Pereira C F, Oliveira C R
Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Largo Marquês de Pombal 3004-517, Coimbra, Portugal.
Int J Cell Biol. 2012;2012:735206. doi: 10.1155/2012/735206. Epub 2012 Jun 4.
Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting several million of people worldwide. Pathological changes in the AD brain include the presence of amyloid plaques, neurofibrillary tangles, loss of neurons and synapses, and oxidative damage. These changes strongly associate with mitochondrial dysfunction and stress of the endoplasmic reticulum (ER). Mitochondrial dysfunction is intimately linked to the production of reactive oxygen species (ROS) and mitochondrial-driven apoptosis, which appear to be aggravated in the brain of AD patients. Concomitantly, mitochondria are closely associated with ER, and the deleterious crosstalk between both organelles has been shown to be involved in neuronal degeneration in AD. Stimuli that enhance expression of normal and/or folding-defective proteins activate an adaptive unfolded protein response (UPR) that, if unresolved, can cause apoptotic cell death. ER stress also induces the generation of ROS that, together with mitochondrial ROS and decreased activity of several antioxidant defenses, promotes chronic oxidative stress. In this paper we discuss the critical role of mitochondrial and ER dysfunction in oxidative injury in AD cellular and animal models, as well as in biological fluids from AD patients. Progress in developing peripheral and cerebrospinal fluid biomarkers related to oxidative stress will also be summarized.
阿尔茨海默病（AD）是老年人痴呆最常见的病因，全球有数百万人受其影响。AD大脑的病理变化包括淀粉样斑块、神经原纤维缠结、神经元和突触丧失以及氧化损伤。这些变化与线粒体功能障碍和内质网（ER）应激密切相关。线粒体功能障碍与活性氧（ROS）的产生以及线粒体驱动的细胞凋亡密切相关，而这在AD患者大脑中似乎更为严重。同时，线粒体与内质网密切相关，两个细胞器之间的有害相互作用已被证明与AD中的神经元变性有关。增强正常和/或折叠缺陷蛋白表达的刺激会激活适应性未折叠蛋白反应（UPR），如果该反应得不到解决，会导致凋亡性细胞死亡。内质网应激还会诱导ROS的产生，ROS与线粒体ROS以及几种抗氧化防御活性的降低共同促进慢性氧化应激。在本文中，我们讨论了线粒体和内质网功能障碍在AD细胞和动物模型以及AD患者生物体液氧化损伤中的关键作用。还将总结与氧化应激相关的外周和脑脊液生物标志物的研究进展。
