Nunomura A, Moreira P I, Lee H G, Zhu X, Castellani R J, Smith M A, Perry G
Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa 078-8510, Japan.
CNS Neurol Disord Drug Targets. 2007 Dec;6(6):411-23. doi: 10.2174/187152707783399201.
Neuronal death is a common feature in neurodegenerative diseases including Alzheimer disease (AD) and Parkinson disease (PD). This occurs over years, not the minutes of classically defined apoptosis, and neurons show both responses of apoptosis and regeneration, evidenced by accumulated oxidative insult and attempts at cell cycle re-entry. There is recent evidence suggesting that several known gene mutations in causing familial AD (amyloid beta protein precursor, presenilin-1, or presenilin-2 gene) and familial PD (Parkin, PINK-1, or DJ-1 gene) are associated with increased oxidative stress. Also, several known genetic (e.g. Apolipoprotein Eepsilon4 variant) and environmental (e.g. metals or pesticides exposure) risk factors of sporadic AD and/or PD are associated with increased oxidative stress. In concord, patients at the preclinical stages of AD and PD as well as cellular and animal models of the diseases provide consistent evidence that oxidative insult is a significant early event in the pathological cascade of AD and PD. In contrast to the general aspects of the pathological hallmarks, aggregation of the disease-specific proteins such as amyloid-beta, tau, and alpha-synuclein may act as a compensatory (survival) response against the oxidative insult via the mechanism that the disease-specific structures sequester redox-active metals. Expanding knowledge of the molecular mechanisms of organism longevity indicates that pro-longevity gene products such as forkhead transcription factors and sirtuins are involved in the insulin-like signaling pathway and oxidative stress resistance against aging. An enhancement of the pro-longevity signaling (e.g. caloric restriction) may be a promising approach as anti-oxidative strategy against age-associated neurodegenerative diseases.
神经元死亡是包括阿尔茨海默病（AD）和帕金森病（PD）在内的神经退行性疾病的一个常见特征。这一过程持续数年，而非经典定义的凋亡过程中的几分钟，并且神经元同时表现出凋亡和再生反应，累积的氧化损伤以及细胞周期重新进入的尝试即为证据。最近有证据表明，导致家族性AD（淀粉样β蛋白前体、早老素-1或早老素-2基因）和家族性PD（帕金蛋白、PINK-1或DJ-1基因）的几种已知基因突变与氧化应激增加有关。此外，散发性AD和/或PD的几种已知遗传（如载脂蛋白Eε4变体）和环境（如接触金属或农药）风险因素也与氧化应激增加有关。与此一致的是，AD和PD临床前期的患者以及这些疾病的细胞和动物模型提供了一致的证据，表明氧化损伤是AD和PD病理级联反应中的一个重要早期事件。与病理特征的一般方面不同，疾病特异性蛋白如淀粉样β蛋白、tau蛋白和α-突触核蛋白的聚集可能通过疾病特异性结构螯合氧化还原活性金属的机制，作为对氧化损伤的一种代偿（生存）反应。对生物体长寿分子机制的认识不断扩展，表明诸如叉头转录因子和沉默调节蛋白等长寿基因产物参与胰岛素样信号通路以及对衰老的氧化应激抵抗。增强长寿信号（如热量限制）可能是一种有前景的抗氧化策略，用于对抗与年龄相关的神经退行性疾病。
