Metal swap between Zn7-metallothionein-3 and amyloid-β-Cu protects against amyloid-β toxicity

Aberrant interactions of copper and zinc ions with the amyloid-beta peptide (A beta) potentiate Alzheimer's disease (AD) by participating in the aggregation process of Ab and in the generation of reactive oxygen species (ROS). The ROS production and the neurotoxicity of Ab are associated with copper binding. Metallothionein-3 (Zn(7)MT-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 Ab. Here, we show that a metal swap between Zn(7)MT-3 and soluble and aggregated A beta(1-40)-Cu(II) abolishes the ROS production and the related cellular toxicity. In this process, copper is reduced by the protein thiolates forming Cu(I)(4)Zn(4)MT-3, in which an air-stable Cu(I)(4)-thiolate cluster and two disulfide bonds are present. The discovered protective effect of Zn(7)MT-3 from the copper-mediated A beta(1-40) toxicity may lead to new therapeutic strategies for treating AD.