Aß(25-35) and its C-and/or N-blocked derivatives: copper driven structural features and neurotoxicity

Bruno Giuseppe Pignataro, Claudia Cascio, Giulia Grasso, Carlo Pedone, Menotti Ruvo, Agata Copani, Maria Laura Giuffrida, Enrico Rizzarelli, Daniela Marasco, Angela Saporito

Risultato della ricerca: Article

27 Citazioni (Scopus)

Abstract

The toxic properties ofb-amyloid protein, Ab(1–42), themajor component of senile plaques in Alzheimer’s dis-ease, depend on nucleation-dependent oligomerizationand aggregation. In addition, Ab(1–42) toxicity isfavored by the presence of trace metals, which affectthe secondary structure of the peptide. A peptide com-prising 11 residues within Ab(1–42) [Ab(25–35)] aggre-gates and retains the neurotoxic activity of Ab(1–42).We have used both Ab(25–35) and its C-amidated orN-acetylated/C-amidated derivatives to investigate therole of copper(II) in modulating the conformation andaggregation state as well as the neurotoxic propertiesof amyloid peptides. Electrospray ionization massspectrometry (ESI-MS) and electron paramagnetic reso-nance (EPR) measurements were performed to verifythe formation of copper(II)/Ab(25–35) complexes and todetermine the coordination mode, respectively. Ab(25–35) and its derivatives were analyzed by circular dichro-ism spectroscopy to assess their secondary structure,subjected to thioflavine-T (Th-T) binding assay to revealb-sheet structured aggregates formation, and imagedby scanning force microscopy. Toxicity was assessedon mature cultures of rat cortical neurons. We foundthatb-sheet-structured species of Ab(25–35) were neu-rotoxic, whereas the random-coil-structured derivativeswere devoid of effect. Interestingly, copper promotedthe random-coil/b-sheet transition of Ab(25–35), withensuing peptide toxicity, but it induced the toxicity ofthe N-acetylated/C-amidated derivative without affect-ing peptide folding. Moreover, copper did not influenceeither the folding or the activity of the C-amidatedAb(25–35), suggesting that blockade of the C-terminusof Abpeptides might be sufficient to prevent
Lingua originaleEnglish
pagine (da-a)623-633
Numero di pagine11
RivistaJournal of Neuroscience Research
Volume85
Stato di pubblicazionePublished - 2007

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Copper
Peptides
Amyloidogenic Proteins
Atomic Force Microscopy
Poisons
Coordination Complexes
Amyloid Plaques
Amyloid
Spectrum Analysis
Metals
Electrons
Neurons

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

Cita questo

Pignataro, B. G., Cascio, C., Grasso, G., Pedone, C., Ruvo, M., Copani, A., ... Saporito, A. (2007). Aß(25-35) and its C-and/or N-blocked derivatives: copper driven structural features and neurotoxicity. Journal of Neuroscience Research, 85, 623-633.

Aß(25-35) and its C-and/or N-blocked derivatives: copper driven structural features and neurotoxicity. / Pignataro, Bruno Giuseppe; Cascio, Claudia; Grasso, Giulia; Pedone, Carlo; Ruvo, Menotti; Copani, Agata; Giuffrida, Maria Laura; Rizzarelli, Enrico; Marasco, Daniela; Saporito, Angela.

In: Journal of Neuroscience Research, Vol. 85, 2007, pag. 623-633.

Risultato della ricerca: Article

Pignataro, BG, Cascio, C, Grasso, G, Pedone, C, Ruvo, M, Copani, A, Giuffrida, ML, Rizzarelli, E, Marasco, D & Saporito, A 2007, 'Aß(25-35) and its C-and/or N-blocked derivatives: copper driven structural features and neurotoxicity', Journal of Neuroscience Research, vol. 85, pagg. 623-633.
Pignataro, Bruno Giuseppe ; Cascio, Claudia ; Grasso, Giulia ; Pedone, Carlo ; Ruvo, Menotti ; Copani, Agata ; Giuffrida, Maria Laura ; Rizzarelli, Enrico ; Marasco, Daniela ; Saporito, Angela. / Aß(25-35) and its C-and/or N-blocked derivatives: copper driven structural features and neurotoxicity. In: Journal of Neuroscience Research. 2007 ; Vol. 85. pagg. 623-633.
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abstract = "The toxic properties ofb-amyloid protein, Ab(1–42), themajor component of senile plaques in Alzheimer’s dis-ease, depend on nucleation-dependent oligomerizationand aggregation. In addition, Ab(1–42) toxicity isfavored by the presence of trace metals, which affectthe secondary structure of the peptide. A peptide com-prising 11 residues within Ab(1–42) [Ab(25–35)] aggre-gates and retains the neurotoxic activity of Ab(1–42).We have used both Ab(25–35) and its C-amidated orN-acetylated/C-amidated derivatives to investigate therole of copper(II) in modulating the conformation andaggregation state as well as the neurotoxic propertiesof amyloid peptides. Electrospray ionization massspectrometry (ESI-MS) and electron paramagnetic reso-nance (EPR) measurements were performed to verifythe formation of copper(II)/Ab(25–35) complexes and todetermine the coordination mode, respectively. Ab(25–35) and its derivatives were analyzed by circular dichro-ism spectroscopy to assess their secondary structure,subjected to thioflavine-T (Th-T) binding assay to revealb-sheet structured aggregates formation, and imagedby scanning force microscopy. Toxicity was assessedon mature cultures of rat cortical neurons. We foundthatb-sheet-structured species of Ab(25–35) were neu-rotoxic, whereas the random-coil-structured derivativeswere devoid of effect. Interestingly, copper promotedthe random-coil/b-sheet transition of Ab(25–35), withensuing peptide toxicity, but it induced the toxicity ofthe N-acetylated/C-amidated derivative without affect-ing peptide folding. Moreover, copper did not influenceeither the folding or the activity of the C-amidatedAb(25–35), suggesting that blockade of the C-terminusof Abpeptides might be sufficient to prevent",
author = "Pignataro, {Bruno Giuseppe} and Claudia Cascio and Giulia Grasso and Carlo Pedone and Menotti Ruvo and Agata Copani and Giuffrida, {Maria Laura} and Enrico Rizzarelli and Daniela Marasco and Angela Saporito",
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T1 - Aß(25-35) and its C-and/or N-blocked derivatives: copper driven structural features and neurotoxicity

AU - Pignataro, Bruno Giuseppe

AU - Cascio, Claudia

AU - Grasso, Giulia

AU - Pedone, Carlo

AU - Ruvo, Menotti

AU - Copani, Agata

AU - Giuffrida, Maria Laura

AU - Rizzarelli, Enrico

AU - Marasco, Daniela

AU - Saporito, Angela

PY - 2007

Y1 - 2007

N2 - The toxic properties ofb-amyloid protein, Ab(1–42), themajor component of senile plaques in Alzheimer’s dis-ease, depend on nucleation-dependent oligomerizationand aggregation. In addition, Ab(1–42) toxicity isfavored by the presence of trace metals, which affectthe secondary structure of the peptide. A peptide com-prising 11 residues within Ab(1–42) [Ab(25–35)] aggre-gates and retains the neurotoxic activity of Ab(1–42).We have used both Ab(25–35) and its C-amidated orN-acetylated/C-amidated derivatives to investigate therole of copper(II) in modulating the conformation andaggregation state as well as the neurotoxic propertiesof amyloid peptides. Electrospray ionization massspectrometry (ESI-MS) and electron paramagnetic reso-nance (EPR) measurements were performed to verifythe formation of copper(II)/Ab(25–35) complexes and todetermine the coordination mode, respectively. Ab(25–35) and its derivatives were analyzed by circular dichro-ism spectroscopy to assess their secondary structure,subjected to thioflavine-T (Th-T) binding assay to revealb-sheet structured aggregates formation, and imagedby scanning force microscopy. Toxicity was assessedon mature cultures of rat cortical neurons. We foundthatb-sheet-structured species of Ab(25–35) were neu-rotoxic, whereas the random-coil-structured derivativeswere devoid of effect. Interestingly, copper promotedthe random-coil/b-sheet transition of Ab(25–35), withensuing peptide toxicity, but it induced the toxicity ofthe N-acetylated/C-amidated derivative without affect-ing peptide folding. Moreover, copper did not influenceeither the folding or the activity of the C-amidatedAb(25–35), suggesting that blockade of the C-terminusof Abpeptides might be sufficient to prevent

AB - The toxic properties ofb-amyloid protein, Ab(1–42), themajor component of senile plaques in Alzheimer’s dis-ease, depend on nucleation-dependent oligomerizationand aggregation. In addition, Ab(1–42) toxicity isfavored by the presence of trace metals, which affectthe secondary structure of the peptide. A peptide com-prising 11 residues within Ab(1–42) [Ab(25–35)] aggre-gates and retains the neurotoxic activity of Ab(1–42).We have used both Ab(25–35) and its C-amidated orN-acetylated/C-amidated derivatives to investigate therole of copper(II) in modulating the conformation andaggregation state as well as the neurotoxic propertiesof amyloid peptides. Electrospray ionization massspectrometry (ESI-MS) and electron paramagnetic reso-nance (EPR) measurements were performed to verifythe formation of copper(II)/Ab(25–35) complexes and todetermine the coordination mode, respectively. Ab(25–35) and its derivatives were analyzed by circular dichro-ism spectroscopy to assess their secondary structure,subjected to thioflavine-T (Th-T) binding assay to revealb-sheet structured aggregates formation, and imagedby scanning force microscopy. Toxicity was assessedon mature cultures of rat cortical neurons. We foundthatb-sheet-structured species of Ab(25–35) were neu-rotoxic, whereas the random-coil-structured derivativeswere devoid of effect. Interestingly, copper promotedthe random-coil/b-sheet transition of Ab(25–35), withensuing peptide toxicity, but it induced the toxicity ofthe N-acetylated/C-amidated derivative without affect-ing peptide folding. Moreover, copper did not influenceeither the folding or the activity of the C-amidatedAb(25–35), suggesting that blockade of the C-terminusof Abpeptides might be sufficient to prevent

UR - http://hdl.handle.net/10447/19388

M3 - Article

VL - 85

SP - 623

EP - 633

JO - Journal of Neuroscience Research

JF - Journal of Neuroscience Research

SN - 0360-4012

ER -