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

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

Research output: Contribution to journalArticle

Abstract

Amyloid β-peptide (Aβ) 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 β-peptide (Aβ) 1-42 (Met35) strongly affects the peptide's ability to trigger apoptosis and is thus a major determinant of its neurotoxicity. Dysregulation of intracellular Ca2+ homeostasis resulting in the activation of pro-apoptotic pathways has been proposed as a mechanism underlying Aβ toxicity. Therefore, we investigated correlations between the Met35 redox state, Aβ toxicity, and altered intracellular Ca2+ signaling in human neuroblastoma IMR32 cells. Cells incubated for 6-24 h with 10 μM Aβ1-42 exhibited significantly increased KCl-induced Ca2+ transient amplitudes and resting free Ca2+ concentrations. Nifedipine-sensitive Ca2+ current densities and Cav1 channel expression were markedly enhanced by Aβ1-42. None of these effects were observed when cells were exposed to Aβ containing oxidized Met35 (Aβ1-42 Met35-Ox). Cell pre-treatment with the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester (1 μM) or the Cav1 channel blocker nifedipine (5 μM) significantly attenuated Aβ1-42-induced apoptosis but had no effect on Aβ1-42Met35-Ox toxicity. Collectively, these data suggest that reduced Met35 plays a critical role in Aβ1-42 toxicity by rendering the peptide capable of disrupting intracellular Ca2+ homeostasis and thereby provoking apoptotic cell death.

Original languageEnglish
Pages (from-to)1070-1082
Number of pages13
JournalJournal of Neurochemistry
Volume107
Issue number4
DOIs
Publication statusPublished - Nov 2008

Keywords

  • Alzheimer's disease
  • Amyloid β-peptide
  • Ca 1 channels
  • Calcium dysregulation
  • Methionine-35
  • Neurotoxicity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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