Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease.
Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease.
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DOI：
10.3233/jad-161088
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Trushina E
中科院分区：
文献类型：
--
作者：
Tönnies E;Trushina E
阿尔茨海默病（AD）是一种无法治愈的破坏性神经退行性疾病。大多数AD病例是散发性的，其中年龄代表最大的风险因素。缺乏对疾病机制的了解阻碍了有效治疗方法的发展。在AD患者中，受影响的脑区域中的突触损失与认知障碍最相关，并且被认为是神经元损失之前的早期机制。氧化应激已被认为是衰老和多种神经退行性疾病（包括AD）进展的一个促成因素。与年龄和疾病依赖性线粒体功能丧失相关的活性氧（ROS）的产生增加，金属稳态改变和抗氧化防御降低直接影响神经元中的突触活性和神经传递，导致认知功能障碍。此外，受ROS影响的分子靶标包括核和线粒体DNA、脂质、蛋白质、钙稳态、线粒体动力学和功能、细胞结构、受体运输和内吞作用以及能量稳态。异常的细胞代谢反过来可以影响淀粉样蛋白-β（A β）和过度磷酸化的Tau蛋白的产生和积累，其独立地可以加剧线粒体功能障碍和ROS产生，从而促成恶性循环。虽然越来越多的证据表明活性氧参与了AD的病因学，但抗氧化治疗的临床试验并未产生一致的结果。在这篇综述中，我们将讨论氧化应激在AD突触功能障碍中的作用，基于对AD分子机制复杂性的更好理解而发展的创新治疗策略，以及ROS在健康和疾病中的双重作用。
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.