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Aβ(25–35) and its C‐ and/or N‐blocked derivatives: Copper driven structural features and neurotoxicity
Author(s) -
Giuffrida Maria Laura,
Grasso Giulia,
Ruvo Menotti,
Pedone Carlo,
Saporito Angela,
Marasco Daniela,
Pignataro Bruno,
Cascio Claudia,
Copani Agata,
Rizzarelli Enrico
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21135
Subject(s) - chemistry , peptide , circular dichroism , random coil , biophysics , neurotoxicity , copper , protein secondary structure , electron paramagnetic resonance , toxicity , amyloid (mycology) , senile plaques , crystallography , stereochemistry , biochemistry , nuclear magnetic resonance , organic chemistry , alzheimer's disease , inorganic chemistry , medicine , physics , disease , pathology , biology
The toxic properties of β‐amyloid protein, Aβ(1–42), the major component of senile plaques in Alzheimer's disease, depend on nucleation‐dependent oligomerization and aggregation. In addition, Aβ(1–42) toxicity is favored by the presence of trace metals, which affect the secondary structure of the peptide. A peptide comprising 11 residues within Aβ(1–42) [Aβ(25–35)] aggregates and retains the neurotoxic activity of Aβ(1–42). We have used both Aβ(25–35) and its C‐amidated or N‐acetylated/C‐amidated derivatives to investigate the role of copper(II) in modulating the conformation and aggregation state as well as the neurotoxic properties of amyloid peptides. Electrospray ionization mass spectrometry (ESI‐MS) and electron paramagnetic resonance (EPR) measurements were performed to verify the formation of copper(II)/Aβ(25–35) complexes and to determine the coordination mode, respectively. Aβ(25–35) and its derivatives were analyzed by circular dichroism spectroscopy to assess their secondary structure, subjected to thioflavine‐T (Th‐T) binding assay to reveal β‐sheet structured aggregates formation, and imaged by scanning force microscopy. Toxicity was assessed on mature cultures of rat cortical neurons. We found that β‐sheet‐structured species of Aβ(25–35) were neurotoxic, whereas the random‐coil‐structured derivatives were devoid of effect. Interestingly, copper promoted the random‐coil/β‐sheet transition of Aβ(25–35), with ensuing peptide toxicity, but it induced the toxicity of the N‐acetylated/C‐amidated derivative without affecting peptide folding. Moreover, copper did not influence either the folding or the activity of the C‐amidated Aβ(25–35), suggesting that blockade of the C‐terminus of Aβ peptides might be sufficient to prevent Aβ toxicity. © 2006 Wiley‐Liss, Inc.