Title : Overexpression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A in nerve cells confers resistance to amyloid beta and other toxins by decreasing mitochondrial respiration and reactive oxygen species production - Newington_2012_J.Biol.Chem_287_37245 |
Author(s) : Newington JT , Rappon T , Albers S , Wong DY , Rylett RJ , Cumming RC |
Ref : Journal of Biological Chemistry , 287 :37245 , 2012 |
Abstract :
We previously demonstrated that nerve cell lines selected for resistance to amyloid beta (Abeta) 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 Abeta and other neurotoxins. Treatment of Abeta-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 Abeta treatment. Interestingly, immunoblot analysis of wild type mouse primary cortical neurons treated with Abeta 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 Alphabeta 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 Abeta deposition without developing Alzheimer disease. |
PubMedSearch : Newington_2012_J.Biol.Chem_287_37245 |
PubMedID: 22948140 |
Newington JT, Rappon T, Albers S, Wong DY, Rylett RJ, Cumming RC (2012)
Overexpression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A in nerve cells confers resistance to amyloid beta and other toxins by decreasing mitochondrial respiration and reactive oxygen species production
Journal of Biological Chemistry
287 :37245
Newington JT, Rappon T, Albers S, Wong DY, Rylett RJ, Cumming RC (2012)
Journal of Biological Chemistry
287 :37245