title: The antioxidant N-acetylcysteine prevents the mitochondrial fragmentation induced by soluble amyloid-β peptide oligomers.
abstract: BACKGROUND
  Soluble amyloid-β peptide oligomers (AβOs), which are centrally involved in the pathogenesis of Alzheimer's disease, trigger Ca(2+) influx through N-methyl-D-aspartate receptors and stimulate reactive oxygen species generation in primary hippocampal neurons. We have previously reported that AβOs promote Ca(2+) release mediated by ryanodine receptors (RyR), which in turn triggers mitochondrial fragmentation. We have also reported that the antioxidant N-acetylcysteine (NAC) prevents AβOs-induced Ca(2+) signal generation.
  
  
  OBJECTIVE
  To determine if RyR-mediated Ca(2+) release activated by the specific agonist 4-chloro-m-cresol (4-CMC) induces fragmentation of the mitochondrial network, and to ascertain if NAC prevents the mitochondrial fragmentation induced by AβOs and/or 4-CMC.
  
  
  METHODS
  Mature primary rat hippocampal neurons were incubated for 24 h with sublethal concentrations of AβOs (500 nM) or for 1-3 h with 4-CMC (0.5-1 mM), ± 10 mM NAC. Mitochondrial morphology was assessed by confocal microscopy of fixed neurons stained with anti-mHsp70. Intracellular Ca(2+) levels were determined by time series microscopy of neurons preloaded with Fluo-4 AM.
  
  
  RESULTS
  Preincubation of neurons for 30 min with NAC prevented the mitochondrial fragmentation induced by AβOs or 4-CMC. In addition, we confirmed that preincubation with NAC abolished the stimulation of RyR-mediated Ca(2+) release induced by AβOs or 4-CMC.
  
  
  CONCLUSIONS
  The present results strongly suggest that the general antioxidant NAC prevents AβO-induced mitochondrial fragmentation by preventing RyR-mediated Ca(2+)-induced Ca(2+) release.
authors.affiliation: Center for Molecular Studies of the Cell, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
authors.forename: C D
authors.initials: CD
authors.lastname: Sanmartin
authors.forename: T
authors.initials: T
authors.lastname: Adasme
authors.forename: C
authors.initials: C
authors.lastname: Hidalgo
authors.forename: A C
authors.initials: AC
authors.lastname: Paula-Lima
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003408:Cresols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D003408:Cresols; D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; C006984:chlorocresol; D002118:Calcium; D000111:Acetylcysteine