title: Methylglyoxal reduces mitochondrial potential and activates Bax and caspase-3 in neurons: Implications for Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by the oxidative stress generated from amyloid β-peptide (Aβ) aggregates. It produces protein nitrotyrosination, after the reaction with nitric oxide to form peroxynitrite, being triosephosphate isomerase (TPI) one of the most affected proteins. TPI is a glycolytic enzyme that catalyzes the interconversion between glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP). Methylglyoxal (MG) is a by-product of TPI activity whose production is triggered when TPI is nitrotyrosinated. MG is harmful to cells because it glycates proteins. Here we found protein glycation when human neuroblastoma cells were treated with Aβ. Moreover glycation was also observed when neuroblastoma cells overexpressed mutated TPI where Tyr165 or Tyr209, the two tyrosines close to the catalytic center, were changed by Phe in order to mimic the effect of nitrotyrosination. The pathological relevance of these findings was studied by challenging cells with Aβ oligomers and MG. A significant decrease in mitochondrial transmembrane potential, one of the first apoptotic events, was obtained. Therefore, increasing concentrations of MG were assayed searching for MG effect in neuronal apoptosis. We found a decrease of the protective Bcl2 and an increase of the proapoptotic caspase-3 and Bax levels. Our results suggest that MG is triggering apoptosis in neurons and it would play a key role in AD neurodegeneration.
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Tajes
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Eraso-Pichot
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Fanny
authors.initials: F
authors.lastname: Rubio-Moscardó
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Biuse
authors.initials: B
authors.lastname: Guivernau
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Bosch-Morató
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Victòria
authors.initials: V
authors.lastname: Valls-Comamala
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF), Barcelona, Spain. Electronic address: paco.munoz@upf.edu.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Muñoz
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D006031:Glycosylation; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity; D011765:Pyruvaldehyde / Q000378:metabolism* / Q000494:pharmacology; D014305:Triose-Phosphate Isomerase / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D051028:bcl-2-Associated X Protein; D011765:Pyruvaldehyde; D053148:Caspase 3; D014305:Triose-Phosphate Isomerase
keywords: 3-Nitrotyrosine; Alzheimer disease; Amyloid; Apoptosis; Methylglyoxal; Triose-phosphate isomerase