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[摘要]：Metal ions, especially Zn2+ and Cu2+, are implemented in the neuropathogenesis of Alzheimer's disease (AD) by modulating the aggregation of amyloid-beta peptides (A beta). 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-A beta 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-A beta-mediated cytotoxicity by a Zn-Cu exchange that terminates ROS production. Key questions about the metal exchange mechanisms remain unanswered, e.g., whether an A beta-metal-MT-3 complex is formed. We studied the exchange of metal between A beta and Zn-7-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 A beta-metal-MT-3 complex is not formed. This means that the metal exchange does not require specific recognition between A beta and Zn-7-MT-3. Also, we found that the metal exchange caused amyloid-related structural and morphological changes in the resulting Zn-A beta aggregates. A detailed model of the metal exchange mechanism is presented. This model could potentially be important in developing therapeutics with metal-protein attenuating properties in AD. |
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