Selective destabilization of soluble amyloid β oligomers by divalent metal ions

Abstract

Aggregation of the amyloid β (Aβ) peptide yields both fibrillar precipitates and soluble oligomers, and is associated with Alzheimer’s disease (AD). In vitro, Cu²⁺ and Zn²⁺ strongly bind Aβ and promote its precipitation. However, less is known about their interactions with the soluble oligomers, which are thought to be the major toxic species responsible for AD. Using fluorescence correlation spectroscopy to resolve the various soluble species of Aβ, we show that low concentrations of Cu²⁺ (1 μM) and Zn²⁺ (4 μM) selectively eliminate the oligomeric population (within ∼2 h), while Mg²⁺ displays a similar effect at a higher concentration (60 μM). This uncovers a new aspect of Aβ–metal ion interactions, as precipitation is not substantially altered at these low metal ion concentrations. Our results suggest that physiological concentrations of Cu²⁺ and Zn²⁺ can critically alter the stability of the toxic Aβ oligomers and can potentially control the course of neurodegeneration.