Overexpression of Pyruvate Dehydrogenase Kinase 1 and Lactate Dehydrogenase A in Nerve Cells Confers Resistance to Amyloid β and Other Toxins by Decreasing Mitochondrial Respiration and Reactive Oxygen Species Production
Overexpression of Pyruvate Dehydrogenase Kinase 1 and Lactate Dehydrogenase A in Nerve Cells Confers Resistance to Amyloid β and Other Toxins by Decreasing Mitochondrial Respiration and Reactive Oxygen Species Production
复制标题
DOI：
10.1074/jbc.m112.366195
复制
发表时间：
2012-10-26
影响因子：
4.8
通讯作者：
Cumming, Robert C.
中科院分区：
文献类型：
--
作者：
Newington, Jordan T.;Rappon, Tim;Cumming, Robert C.
我们先前证明，选择对淀粉样β（A β）肽具有抗性的神经细胞系表现出有氧糖酵解升高，部分原因是丙酮酸脱氢酶激酶1（PDK 1）和乳酸脱氢酶A（LDHA）表达增加。在这里，我们表明，PDK 1或LDHA在大鼠CNS细胞系（B12）中的过度表达赋予了对A β和其他神经毒素的抗性。用各种毒素处理A β敏感细胞导致线粒体超极化，随后立即发生快速去极化和细胞死亡，事件伴随着细胞活性氧（ROS）的产生增加。相比之下，表达PDK 1或LDHA的细胞在暴露或不暴露于毒素的情况下保持较低的线粒体膜电位并减少ROS产生。此外，在正常培养条件下和A β处理后，PDK 1和LDH过表达细胞的耗氧量降低，但ATP水平保持不变。有趣的是，与对照组相比，用A β或来自12月龄APPswe/PS1 dE 9转基因小鼠的皮质组织提取物处理的野生型小鼠原代皮质神经元的免疫印迹分析显示LDHA和PDK 1的表达降低。此外，与非痴呆患者相比，阿尔茨海默病患者的死后脑提取物显示PDK 1表达减少。总的来说，这些发现表明，关键的瓦尔堡效应酶通过降低线粒体活性和随后的ROS产生，在介导神经元对A β或其他神经毒素的抗性中发挥核心作用。PDK 1或LDHA在大脑某些区域的表达的维持可以解释为什么一些人耐受高水平的A β沉积而不发展为阿尔茨海默病。
We previously demonstrated that nerve cell lines selected for resistance to amyloid beta (A beta) peptide exhibit elevated aerobic glycolysis in part due to increased expression of pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA). Here, we show that overexpression of either PDK1 or LDHA in a rat CNS cell line (B12) confers resistance to A beta and other neurotoxins. Treatment of A beta-sensitive cells with various toxins resulted in mitochondrial hyperpolarization, immediately followed by rapid depolarization and cell death, events accompanied by increased production of cellular reactive oxygen species (ROS). In contrast, cells expressing either PDK1 or LDHA maintained a lower mitochondrial membrane potential and decreased ROS production with or without exposure to toxins. Additionally, PDK1- and LDHA-overexpressing cells exhibited decreased oxygen consumption but maintained levels of ATP under both normal culture conditions and following A beta treatment. Interestingly, immunoblot analysis of wild type mouse primary cortical neurons treated with A beta or cortical tissue extracts from 12-month-old APPswe/PS1dE9 transgenic mice showed decreased expression of LDHA and PDK1 when compared with controls. Additionally, post-mortem brain extracts from patients with Alzheimer disease exhibited a decrease in PDK1 expression compared with nondemented patients. Collectively, these findings indicate that key Warburg effect enzymes play a central role in mediating neuronal resistance to A beta or other neurotoxins by decreasing mitochondrial activity and subsequent ROS production. Maintenance of PDK1 or LDHA expression in certain regions of the brain may explain why some individuals tolerate high levels of A beta deposition without developing Alzheimer disease.