title: 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.
abstract: We previously demonstrated that nerve cell lines selected for resistance to amyloid β (Aβ) 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 Aβ and other neurotoxins. Treatment of Aβ-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 Aβ treatment. Interestingly, immunoblot analysis of wild type mouse primary cortical neurons treated with Aβ 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 Αβ 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 Aβ deposition without developing Alzheimer disease.
authors.affiliation: Department of Biology, University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Newington
authors.forename: Tim
authors.initials: T
authors.lastname: Rappon
authors.forename: Shawn
authors.initials: S
authors.lastname: Albers
authors.forename: Daisy Y
authors.initials: DY
authors.lastname: Wong
authors.forename: R Jane
authors.initials: RJ
authors.lastname: Rylett
authors.forename: Robert C
authors.initials: RC
authors.lastname: Cumming
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D019069:Cell Respiration; D002540:Cerebral Cortex / Q000201:enzymology; D005260:Female; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology*; D010101:Oxygen Consumption; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D007527:Isoenzymes; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; C000631434:Pdk1 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine