Metal swap between Zn7metallothionein-3 and amyloid-β-Cu protects against amyloid-β toxicity Meloni, G; Sonois, V; Delaine, T; Guilloreau , L; Gillet, A; Teissie, J; Faller, P; Vasak, M Meloni, G; Sonois, V; Delaine, T; Guilloreau , L; Gillet, A; Teissie, J; Faller, P; Vasak, M (2008). Metal swap between Zn7metallothionein-3 and amyloid-β-Cu protects against amyloid-β toxicity. Nature Chemical Biology, 4 Metal swap between Zn7metallothionein-3 and amyloid-β-Cu protects against amyloid-β toxicity Abstract Aberrant interactions of copper and zinc ions with the amyloid-β peptide (Aβ) potentiate Alzheimer disease (AD) by participating in the aggregation process of Aβ and in thegeneration of reactive oxygen species (ROS). The ROS production and the neurotoxicity of Aβ are associated with copper binding. Metallothionein-3 (Zn7MT-3), an intra-andextracellularly occurring metalloprotein, is highly expressed in the brain and down-regulated in AD. This protein protects, by an unknown mechanism, cultured neurons from the toxicity of Aβ. Herein, 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 newtherapeutic strategies in treating AD.Metal swap between Zn 7 metallothionein-3 and amyloid-β-Cu protects against amyloid-β toxicity residue Aβ peptide, a proteolytic fragment generated from the amyloid precursor protein (APP)by β-and γ-secretases 1 . There is significant evidence indicating that the Aβ peptides can interact with metal ions such as Zn(II) and Cu(II), thereby participating in their aggregation and in the production of ROS 1, 2 . Whereas the copper-induced Aβ aggregation is related to the ROS production and neurotoxicity 3 , the zinc-induced Aβ aggregation is considered to be neuroprotective 4 . The ROS are generated by Aβ-Cu(II) through the redox cycling of copper which requires its reduction by biological components such as ascorbate (1), glutathione (2), dopamine (3), and cholesterol (4) 5,6 . A dysregulation of metal ion homeostasis, as occurs in AD, may foster an environment that promotes such degenerative conditions. The modulation of brain metal ion homeostasis, the reduction of aberrant metal-protein interactions by MPAC (metal-
