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Issue 7, 2017
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Identification of key structural features of the elusive Cu–Aβ complex that generates ROS in Alzheimer’s disease

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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, denoted the “catalytic in-between state” (CIBS), which is in equilibrium with the resting state (RS) of both 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 and NMR) to characterize the binding of Cu to a wide series of modified peptides in the RS. ROS production by the resulting Cu–peptide complexes was evaluated using fluorescence and UV-vis based methods and led to the identification of the amino acid residues involved in the Cu–Aβ CIBS species. In addition, a possible mechanism by which the ROS are produced is also proposed. These two main results are expected to affect the current vision of the ROS production mechanism by Cu–Aβ but also in other diseases involving amyloidogenic peptides with weakly structured copper binding sites.

Graphical abstract: Identification of key structural features of the elusive Cu–Aβ complex that generates ROS in Alzheimer’s disease

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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., 2017,8, 5107-5118
  • Open access: Creative Commons BY-NC license
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    Identification of key structural features of the elusive Cu–Aβ complex that generates ROS in Alzheimer’s disease

    C. Cheignon, M. Jones, E. Atrián-Blasco, I. Kieffer, P. Faller, F. Collin and C. Hureau, Chem. Sci., 2017, 8, 5107
    DOI: 10.1039/C7SC00809K

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