Lovell M A, Xie C, Gabbita S P, Markesbery W R
Sanders-Brown Center on Aging, Departments of Chemistry, Neurology, and Pathology, University of Kentucky, Lexington, KY 40536-0230, USA.
Free Radic Biol Med. 2000 Feb 1;28(3):418-27. doi: 10.1016/s0891-5849(99)00258-0.
Increasing evidence supports the role of reactive oxygen species (ROS) in the pathogenesis of Alzheimer's disease (AD). Both in vivo and in vitro studies demonstrate that thioredoxin (Trx) and thioredoxin reductase (TR), the enzyme responsible for reduction of oxidized Trx, have protective roles against cytotoxicity mediated by the generation of ROS. The present study measured levels of Trx protein and activities of TR in the brain in AD compared with control subjects, and evaluated the possible protective role of TR and Trx against amyloid beta-peptide (Abeta) toxicity in neuronal cultures. Analysis of Trx protein levels in 10 AD and 10 control subjects demonstrated a general decrease in all AD brain regions studied, with statistically significant decreases in the amygdala (p <.05), hippocampus/parahippocampal gyrus (p <.05), and marginally significant (p <.10) depletions in the superior and middle temporal gryi. Thioredoxin reductase activity levels were increased in all AD brain regions studied with statistically significant increases occurring in AD amygdala (p =.01) and cerebellum (p =.007). To investigate the protective effects of Trx and TR against Abeta-induced toxicity, primary hippocampal cultures were treated with Trx or TR in combination with toxic doses of Abeta. Treatment of cultures with Trx led to a statistically significant concentration-dependent enhancement in cell survival against Abeta-mediated toxicity as did treatment with TR. Together, these data suggest that, although TR is protective against Abeta-mediated toxicity, the increase observed in AD brain offers no protection due to the significant decrease in Trx levels. This decrease in the antioxidant Trx-TR system may contribute to the increased oxidative stress and subsequent neurodegeneration observed in the brain in AD.
越来越多的证据支持活性氧（ROS）在阿尔茨海默病（AD）发病机制中的作用。体内和体外研究均表明，硫氧还蛋白（Trx）和负责还原氧化型Trx的酶——硫氧还蛋白还原酶（TR），对由ROS生成介导的细胞毒性具有保护作用。本研究测量了AD患者与对照受试者大脑中Trx蛋白水平和TR活性，并评估了TR和Trx对神经元培养物中β淀粉样肽（Aβ）毒性的可能保护作用。对10例AD患者和10例对照受试者的Trx蛋白水平分析表明，在所研究的所有AD脑区中，Trx蛋白水平普遍下降，杏仁核（p <.05）、海马/海马旁回（p <.05）有统计学显著下降，颞上回和颞中回有边缘性显著（p <.10）减少。在所研究的所有AD脑区中，硫氧还蛋白还原酶活性水平均升高，AD杏仁核（p =.01）和小脑（p =.007）有统计学显著升高。为了研究Trx和TR对Aβ诱导毒性的保护作用，将原代海马培养物用Trx或TR与毒性剂量的Aβ联合处理。用Trx处理培养物导致细胞存活对Aβ介导毒性的浓度依赖性增强，具有统计学显著性，TR处理也有同样效果。总之，这些数据表明，尽管TR对Aβ介导的毒性具有保护作用，但在AD脑中观察到的TR增加由于Trx水平的显著下降而没有提供保护。抗氧化Trx-TR系统的这种下降可能导致AD脑中观察到的氧化应激增加和随后的神经退行性变。
