Role of methionine 35 in the intracellular Ca2+ homeostasis dysregulation and Ca2+ -dependent apoptosis induced by amyloid beta-peptide in human neuroblastoma IMR32 cells.

Roberto Piacentini, Cristian Ripoli, Lucia Leone, Marcello D'Ascenzo, Gian Battista Azzena, Claudio Grassi, Francesco Misiti, Maria Elisabetta Clementi, Bruno Giardina

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26 Citations (Scopus)

Abstract

Amyloid beta-peptide (Abeta) plays a fundamental role in the pathogenesis of Alzheimer's disease. We recently reported that the redox state of the methionine residue in position 35 of amyloid beta-peptide (Abeta) 1-42 (Met35) strongly affects the peptide's ability to trigger apoptosis and is thus a major determinant of its neurotoxicity. Dysregulation of intracellular Ca(2+) homeostasis resulting in the activation of pro-apoptotic pathways has been proposed as a mechanism underlying Abeta toxicity. Therefore, we investigated correlations between the Met35 redox state, Abeta toxicity, and altered intracellular Ca(2+) signaling in human neuroblastoma IMR32 cells. Cells incubated for 6-24 h with 10 microM Abeta1-42 exhibited significantly increased KCl-induced Ca(2+) transient amplitudes and resting free Ca(2+) concentrations. Nifedipine-sensitive Ca(2+) current densities and Ca(v)1 channel expression were markedly enhanced by Abeta1-42. None of these effects were observed when cells were exposed to Abeta containing oxidized Met35 (Abeta1-42(Met35-Ox)). Cell pre-treatment with the intracellular Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (1 microM) or the Ca(v)1 channel blocker nifedipine (5 microM) significantly attenuated Abeta1-42-induced apoptosis but had no effect on Abeta1-42(Met35-Ox) toxicity. Collectively, these data suggest that reduced Met35 plays a critical role in Abeta1-42 toxicity by rendering the peptide capable of disrupting intracellular Ca(2+) homeostasis and thereby provoking apoptotic cell death.
Original languageEnglish
Pages (from-to)1070-1082
Number of pages13
JournalJournal of Neurochemistry
Volume107 (4)
DOIs
Publication statusPublished - 2008

Keywords

  • Amyloid beta protein
  • Cav1
  • calcium
  • methionine35

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