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

• Published in: The Journal of biological chemistry 2012-10, Vol.287 (44), p.37245-37258
• Main Authors: Newington, Jordan T., Rappon, Tim, Albers, Shawn, Wong, Daisy Y., Rylett, R.Jane, Cumming, Robert C.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Aerobic Glycolysis; Aged; Aged, 80 and over; Alzheimer Disease; Alzheimer Disease - enzymology; Amyloid; Amyloid beta-Peptides - physiology; Animals; Brain Metabolism; Case-Control Studies; Cell Line; Cell Respiration; Cerebral Cortex - enzymology; Female; Gene Expression; Humans; Hydrogen Peroxide - pharmacology; Isoenzymes - genetics; Isoenzymes - metabolism; L-Lactate Dehydrogenase - genetics; L-Lactate Dehydrogenase - metabolism; Lactate Dehydrogenase 5; Lactate Dehydrogenase A; Male; Membrane Potential, Mitochondrial; Mice; Mice, Transgenic; Mitochondria - metabolism; Mitochondrial Metabolism; Molecular Bases of Disease; Neurons - enzymology; Oxidative Stress; Oxygen Consumption; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Pyruvate Dehydrogenase Kinase; Rats; Reactive Oxygen Species (ROS); Reactive Oxygen Species - metabolism; Staurosporine - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.366195

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. Background: Aerobic glycolysis promotes resistance against Aβ toxicity. Results: Increased LDHA and PDK1 expression attenuates mitochondrial activity and confers resistance to Aβ. These proteins are down-regulated in a transgenic Alzheimer disease (AD) mouse model, and PDK1 is decreased in AD brain. Conclusion: PDK and LDHA are central mediators of Aβ resistance. Significance: Drugs that augment aerobic glycolysis may enhance brain cell survival in AD patients.