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Identification of key structural features of the elusive Cu-Aβ complex generating ROS in Alzheimer’s Disease

Abstract

Oxidative stress is linked to the etiology of Alzheimer’s disease (AD), the most common cause of dementia in the elderly. Redox active metal ions such as copper catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ) peptide encountered in AD. We propose that this reaction proceeds through a low-populated Cu-Aβ state, noted “catalytic in-between state” (CIBS) in equilibrium with the resting states (RS) of Cu(I)-Aβ and Cu(II)-Aβ. The nature of this CIBS is investigated in the present work. We report the use of complementary spectroscopic methods (X-ray absorption spectroscopy, EPR, NMR) to characterize Cu binding to a wide series of modified peptides in the RS. The ROS production by the resulting Cu-peptides complexes was evaluated by fluorescence and UV-Vis-based methods leading to the identification of the amino acid residues involved in the CIBS Cu-Aβ species. In addition, a possible mechanism by which the ROS are produced is also proposed. These two main fallouts are expected to impact the current vision of the ROS production mechanism by Cu-Aβ but also in any other diseases involving amyloidogenic peptides with weakly structured copper binding sites.

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Publication details

The article was received on 20 Feb 2017, accepted on 29 Apr 2017 and first published on 04 May 2017


Article type: Edge Article
DOI: 10.1039/C7SC00809K
Citation: Chem. Sci., 2017, Accepted Manuscript
  • Open access: Creative Commons BY-NC license
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    Identification of key structural features of the elusive Cu-Aβ complex generating ROS in Alzheimer’s Disease

    C. Cheignon, M. Jones, E. Atrián-Blasco, I. Kieffer, P. Faller, F. Collin and C. Hureau, Chem. Sci., 2017, Accepted Manuscript , DOI: 10.1039/C7SC00809K

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