Rapid Exchange of Metal between Zn7–Metallothionein-3 and Amyloid-β Peptide Promotes Amyloid-Related Structural Changes

Metal ions, especially Zn2+ and Cu2+, are implemented in the neuropathogenesis of Alzheimer’s disease (AD) by modulating the aggregation of amyloid-β peptides (Aβ). Also, Cu2+ may promote AD neurotoxicity through production of reactive oxygen species (ROS). Impaired metal ion homeostasis is most likely the underlying cause of aberrant metal–Aβ interaction. Thus, focusing on the body’s natural protective mechanisms is an attractive therapeutic strategy for AD. The metalloprotein metallothionein-3 (MT-3) prevents Cu–Aβ-mediated cytotoxicity by a Zn–Cu exchange that terminates ROS production. Key questions about the metal exchange mechanisms remain unanswered, e.g., whether an Aβ–metal–MT-3 complex is formed. We studied the exchange of metal between Aβ and Zn7–MT-3 by a combination of spectroscopy (absorption, fluorescence, thioflavin T assay, and nuclear magnetic resonance) and transmission electron microscopy. We found that the metal exchange occurs via free Cu2+ and that an Aβ–metal–MT-3 complex is not fo...