Stoichiometric Zn 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 Zn have been shown to be closely involved in modulating Aβ self-association. Although the link between Zn dyshomeostasis and brain Aβ deposition has been established, the effect of Zn 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 Zn on the aggregation process of Aβ42, the main toxic isoform of Aβ species in the brain. Aβ42 aggregates found in the presence of Zn were smaller in size, non-fibrillary and showed less β-sheet structures than aggregates formed in absence of Zn. AUC showed that Zn was capable of retaining monomeric Aβ42 in solution. Zn chelation by EDTA totally reversed the inhibitory effect of Zn on Aβ42 fibrillation. Our results provide further evidence that Zn shifts the self-association of Aβ42 toward a non-fibrillary pathway by interfering with the aggregation process at multiple levels.