Abstract
The presence of trace concentrations of metallic ions, such as copper and zinc, has previously been shown to drastically increase the aggregation rate and neurotoxicity of amyloid-β (Aβ), the peptide implicated in Alzheimer’s disease (AD). The mechanism of why copper and zinc accelerate Aβ aggregation is poorly understood. In this work, we use single molecule force spectroscopy (SMFS) to probe the kinetic and thermodynamic parameters (dissociation constant, Kd, kinetic dissociation rate, koff, and free energy, ΔG) of the dissociation of an Aβ dimer, the amyloid species which initiates the amyloid cascade. Our results show that nanomolar concentrations of copper do not change the single molecule affinity of Aβ to another Aβ peptide in a statistically significant way, while nanomolar concentrations of zinc decrease the affinity of Aβ-Aβ by an order of magnitude. This suggests that the binding of zinc ion to Aβ may interfere with the binding of Aβ-Aβ, leading to a lower self-affinity.
Highlights
We characterized the effect of trace concentrations of copper (Cu2+) and zinc (Zn2+) ions on the dissociation constant, Kd, kinetic dissociation rate, koff, and the difference in free energy between the bound and unbound states, ΔG, of the dissociation of two amyloid-β (1–42) (Aβ42) monomers forming an amyloid dimer, the smallest neurotoxic species implicated in Alzheimer’s disease (AD) [1]
As the two monomers are mechanically dissociated at various loading rates, the dissociation rate increases exponentially to the natural logarithm of the rupture force, while the association rate decreases with increasing rupture force [34]
To further understand the effect of metal ions on amyloid aggregation, we studied the effect of nanomolar concentrations of Cu2+ and Zn2+ ions, an environment roughly analogous to the environment resulting from metal dyshomeostasis which occurs in AD patients
Summary
We characterized the effect of trace concentrations of copper (Cu2+) and zinc (Zn2+) ions on the dissociation constant, Kd, kinetic dissociation rate, koff, and the difference in free energy between the bound and unbound states, ΔG, of the dissociation of two amyloid-β (1–42) (Aβ42) monomers forming an amyloid dimer, the smallest neurotoxic species implicated in Alzheimer’s disease (AD) [1]. AD is a neurodegenerative disease believed to be caused by the aggregation of the Aβ peptide into toxic oligomers [4,5,6]. These toxic oligomers can take the form of a variety of different morphologies including prefibrillar oligomers, amyloid derived diffusible ligands and annular protofibrils [7]. The first initial step in the formation of these oligomers and fibrils is binding of PLOS ONE | DOI:10.1371/journal.pone.0147488 January 25, 2016
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