Lee Wei-Hua, Kumar Ashok, Rani Asha, Foster Thomas C
Department of Medical Genetics, University of Wisconsin, Madison, WI, USA.
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Neurobiol Aging. 2014 Jun;35(6):1459-68. doi: 10.1016/j.neurobiolaging.2013.12.002. Epub 2013 Dec 9.
Overexpression of superoxide dismutase 1 (SOD1) in the hippocampus results in age-dependent impaired cognition and altered synaptic plasticity suggesting a possible model for examining the role of oxidative stress in senescent neurophysiology. However, it is unclear if SOD1 overexpression involves an altered redox environment and a decrease in N-methyl-D-aspartate receptor (NMDAR) synaptic function reported for aging animals. Viral vectors were used to express SOD1 and green fluorescent protein (SOD1 + GFP), SOD1 and catalase (SOD1 + CAT), or GFP alone in the hippocampus of middle-aged (17 months) male Fischer 344 rats. We confirm that SOD1 + GFP and SOD1 + CAT reduced lipid peroxidation indicating superoxide metabolites were primarily responsible for lipid peroxidation. SOD1 + GFP impaired learning, decreased glutathione peroxidase activity, decreased glutathione levels, decreased NMDAR-mediated synaptic responses, and impaired long-term potentiation. Co-expression of SOD1 + CAT rescued the effects of SOD1 expression on learning, redox measures, and synaptic function suggesting the effects were mediated by excess hydrogen peroxide. Application of the reducing agent dithiolthreitol to hippocampal slices increased the NMDAR-mediated component of the synaptic response in SOD1 + GFP animals relative to animals that overexpress SOD1 + CAT indicating that the effect of antioxidant enzyme expression on NMDAR function was because of a shift in the redox environment. The results suggest that overexpression of neuronal SOD1 and CAT in middle age may provide a model for examining the role of oxidative stress in senescent physiology and the progression of age-related neurodegenerative diseases.
海马体中超氧化物歧化酶1（SOD1）的过表达会导致年龄依赖性认知障碍和突触可塑性改变，这提示了一个用于研究氧化应激在衰老神经生理学中作用的可能模型。然而，目前尚不清楚SOD1过表达是否涉及氧化还原环境的改变以及衰老动物中报道的N-甲基-D-天冬氨酸受体（NMDAR）突触功能的降低。使用病毒载体在中年（17个月）雄性Fischer 344大鼠的海马体中表达SOD1和绿色荧光蛋白（SOD1 + GFP）、SOD1和过氧化氢酶（SOD1 + CAT）或单独的GFP。我们证实SOD1 + GFP和SOD1 + CAT降低了脂质过氧化，表明超氧化物代谢产物是脂质过氧化的主要原因。SOD1 + GFP损害学习能力，降低谷胱甘肽过氧化物酶活性、谷胱甘肽水平、NMDAR介导的突触反应，并损害长期增强效应。SOD1 + CAT的共表达挽救了SOD1表达对学习、氧化还原指标和突触功能的影响，这表明这些影响是由过量过氧化氢介导的。将还原剂二硫苏糖醇应用于海马体切片，相对于过表达SOD1 + CAT的动物，增加了SOD1 + GFP动物中突触反应的NMDAR介导成分，这表明抗氧化酶表达对NMDAR功能的影响是由于氧化还原环境的改变。结果表明，中年时神经元SOD1和CAT的过表达可能为研究氧化应激在衰老生理学和年龄相关神经退行性疾病进展中的作用提供一个模型。
