Stoichiometric Zn²⁺ interferes with the self-association of Aβ42: Insights from size distribution analysis

The abnormal aggregation of amyloid β (Aβ) peptides in the brain has been recognized as a central event in Alzheimer's disease (AD). Divalent metal ions such as Zn²⁺ have been shown to be closely involved in modulating Aβ self-association. Although the link between Zn²⁺ dyshomeostasis and brain Aβ deposition has been established, the effect of Zn²⁺ on the aggregation of Aβ is still incompletely clarified. By combining analytical ultracentrifugation (AUC), circular dichroism (CD) spectroscopy, thioflavin T (ThT) assay and atomic force microscopy (AFM) imaging, we analyzed the impact of stoichiometric Zn²⁺ on the aggregation process of Aβ42, the main toxic isoform of Aβ species in the brain. Aβ42 aggregates found in the presence of Zn²⁺ were smaller in size, non-fibrillary and showed less β-sheet structures than aggregates formed in absence of Zn²⁺. AUC showed that Zn²⁺ was capable of retaining monomeric Aβ42 in solution. Zn²⁺ chelation by EDTA totally reversed the inhibitory effect of Zn²⁺ on Aβ42 fibrillation. Our results provide further evidence that Zn²⁺ shifts the self-association of Aβ42 toward a non-fibrillary pathway by interfering with the aggregation process at multiple levels.