Abstract
Aberrant interactions of copper and zinc ions with the amyloid-β peptide (Aβ) potentiate Alzheimer's disease (AD) by participating in the aggregation process of Aβ and in the generation of reactive oxygen species (ROS). The ROS production and the neurotoxicity of Aβ are associated with copper binding. Metallothionein-3 (Zn7MT-3), an intra- and extracellularly occurring metalloprotein, is highly expressed in the brain and downregulated in AD. This protein protects, by an unknown mechanism, cultured neurons from the toxicity of Aβ. Here, we show that a metal swap between Zn7MT-3 and soluble and aggregated Aβ1–40–Cu(II) abolishes the ROS production and the related cellular toxicity. In this process, copper is reduced by the protein thiolates forming Cu(I)4Zn4MT-3, in which an air-stable Cu(I)4-thiolate cluster and two disulfide bonds are present. The discovered protective effect of Zn7MT-3 from the copper-mediated Aβ1–40 toxicity may lead to new therapeutic strategies for treating AD.
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Acknowledgements
This work was supported by Action-Concertée-Integrée INTERFACE Physique-Chimie-Biologie (P.F.), Swiss National Science Foundation grant 3100A0–100246/1 (M.V.), Programme d'Actions Intégrées Germaine de Staël grants 08345VK (M.V. and P.F.) and the Hartmann Müller-Stiftung (M.V.). We thank A. Mari and L. Rechignat for EPR measurements, D. Lavabre for preliminary luminescence experiments and E. Bellard and M. Fix for help in cell viability experiments. We also thank S. Chesnov for recording nano-ESI-MS spectra.
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Meloni, G., Sonois, V., Delaine, T. et al. Metal swap between Zn7-metallothionein-3 and amyloid-β–Cu protects against amyloid-β toxicity. Nat Chem Biol 4, 366–372 (2008). https://doi.org/10.1038/nchembio.89
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DOI: https://doi.org/10.1038/nchembio.89
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