Effect of Copper and Zinc on the Single Molecule Self-Affinity of Alzheimer's Amyloid-β Peptides

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-beta (A beta), the peptide implicated in Alzheimer's disease (AD). The mechanism of why copper and zinc accelerate A beta aggregation is poorly understood. In this work, we use single molecule force spectroscopy (SMFS) to probe the kinetic and thermodynamic parameters (dissociation constant, K-d, kinetic dissociation rate, k(off), and free energy, Delta G) of the dissociation of an A beta 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 A beta to another A beta peptide in a statistically significant way, while nanomolar concentrations of zinc decrease the affinity of A beta-A beta by an order of magnitude. This suggests that the binding of zinc ion to A beta may interfere with the binding of A beta-A beta, leading to a lower self-affinity.