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.

Piacentini, R., Ripoli, C., Leone, L., Misiti, F., Clementi, M. E., D'ascenzo, M., Giardina, B., Azzena, G. B., Grassi, C., Role of methionine 35 in the intracellular Ca2+ homeostasis dysregulation and Ca2+ -dependent apoptosis induced by amyloid beta-peptide in human neuroblastoma IMR32 cells., <<JOURNAL OF NEUROCHEMISTRY>>, 2008; 107 (4) (Novembre): 1070-1082. [doi:10.1111/j.1471-4159.2008.05680.x] [http://hdl.handle.net/10807/31384]

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

Piacentini, Roberto;Ripoli, Cristian;Leone, Lucia;Misiti, Francesco;Clementi, Maria Elisabetta;D'Ascenzo, Marcello;Giardina, Bruno;Azzena, Gian Battista;Grassi, Claudio
2008

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.
Inglese
Piacentini, R., Ripoli, C., Leone, L., Misiti, F., Clementi, M. E., D'ascenzo, M., Giardina, B., Azzena, G. B., Grassi, C., Role of methionine 35 in the intracellular Ca2+ homeostasis dysregulation and Ca2+ -dependent apoptosis induced by amyloid beta-peptide in human neuroblastoma IMR32 cells., <<JOURNAL OF NEUROCHEMISTRY>>, 2008; 107 (4) (Novembre): 1070-1082. [doi:10.1111/j.1471-4159.2008.05680.x] [http://hdl.handle.net/10807/31384]
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