Histidine availability is decisive in ROS-mediated cytotoxicity of copper complexes of Aβ1–16 peptide

Abstract

The binding of metal ions to Aβ peptide plays an important role in the etiology of AD. Copper coordinates chiefly to His residues and produces reactive oxygen species (ROS) upon redox cycling. ROS builds enormous burden on the normal functioning of neuronal cells and results into deleterious effects. Recently, two structurally distinct copper binding sites with contrasting redox properties were characterized. Here, we demonstrate for the first time the effect of binding of two equivalents of Cu²⁺ on redox properties and cytotoxicity of Aβ peptide. Our electrochemical data and ascorbate consumption assay suggest that in the presence of two equivalents of copper; Aβ peptide has higher propensity of H₂O₂ generation. The oxidation of Aβ1–16 peptide due to both gamma radiolysis and metal catalyzed oxidation in the presence of two equivalents of copper is inhibited confirming the binding of both equivalents of copper to peptide. The electrochemical and cytotoxicity study shows that negative shift in the reduction potential is reflected as slightly higher cytotoxicity in SH-SY5Y cell lines for Aβ1–16–Cu²⁺ (1:2) complex.

KEYWORDS:

• Alzheimer’s disease
• amyloid β
• copper
• cytotoxicity
• reactive oxygen species

Acknowledgements

Authors thank Mrs. A. A. Athawale, Department of Chemistry, S. P. Pune University for gamma radiolysis facility, Ms. Snigdha Dhali, Proteomics Laboratory, NCCS for the technical assistance in mass spectral measurements, and Dr. K. M. Paknikar, Director, Agharkar Research Institute for their support.

Declaration of interest

This work was supported by the funds from Department of Science and Technology (SR/S1/IC-30/2010) and Department of Biotechnology, India (BT/PR3871/MED/30/830/2012). YPG thanks CSIR, Government of India for SRF and SNR thanks UGC, Government of India for SRF.