Mattson Mark P
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, USA.
Antioxid Redox Signal. 2006 Nov-Dec;8(11-12):1997-2006. doi: 10.1089/ars.2006.8.1997.
When subjected to excessive oxidative stress, neurons may respond adaptively to overcome the stress, or they may activate a programmed cell death pathway called apoptosis. Apoptosis is characterized by alterations in mitochondria and the endoplasmic reticulum and activation of cysteine proteases called caspases. Increasing evidence suggests that apoptotic biochemical cascades are involved in the dysfunction and death of neurons in neurodegenerative disorders such as Alzheimer's, Parkinson, and Huntington's diseases. Studies of normal aging, of genetic mutations that cause disease, and of environmental factors that affect disease risk are revealing cellular and molecular alterations that may cause excessive oxidative stress and trigger neuronal apoptosis. Accumulation of self-aggregating proteins such as amyloid beta-peptide, tau, alpha-synuclein, and huntingtin may be involved in apoptosis both upstream and downstream of oxidative stress. Membrane-associated oxidative stress resulting in perturbed lipid metabolism and disruption of cellular calcium homeostasis may trigger apoptosis in several different neurodegenerative disorders. Counteracting neurodegenerative processes are an array of mechanisms including neurotrophic factor signaling, antioxidant enzymes, protein chaperones, antiapoptotic proteins, and ionostatic systems. Emerging findings suggest that the resistance of neurons to death during aging can be enhanced by modifications of diet and lifestyle.
当受到过度氧化应激时，神经元可能会做出适应性反应以克服这种应激，或者它们可能会激活一种称为凋亡的程序性细胞死亡途径。凋亡的特征是线粒体和内质网发生改变，以及半胱天冬酶（一类半胱氨酸蛋白酶）的激活。越来越多的证据表明，凋亡的生化级联反应参与了神经退行性疾病（如阿尔茨海默病、帕金森病和亨廷顿舞蹈病）中神经元的功能障碍和死亡。对正常衰老、导致疾病的基因突变以及影响疾病风险的环境因素的研究，正在揭示可能导致过度氧化应激并引发神经元凋亡的细胞和分子改变。自我聚集蛋白（如β-淀粉样肽、tau蛋白、α-突触核蛋白和亨廷顿蛋白）的积累可能在氧化应激的上游和下游参与凋亡过程。导致脂质代谢紊乱和细胞钙稳态破坏的膜相关氧化应激可能在几种不同的神经退行性疾病中引发凋亡。一系列机制（包括神经营养因子信号传导、抗氧化酶、蛋白质伴侣、抗凋亡蛋白和离子稳态系统）可对抗神经退行性过程。新出现的研究结果表明，通过改变饮食和生活方式可以增强神经元在衰老过程中的抗死亡能力。
