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

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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
Lingua originaleEnglish
pagine (da-a)623-633
Numero di pagine11
RivistaJournal of Neuroscience Research
Volume85
Stato di pubblicazionePublished - 2007

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

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    Pignataro, B. G., Cascio, C., Grasso, G., Pedone, C., Ruvo, M., Copani, A., Giuffrida, M. L., 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, 85, 623-633.