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

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.

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

“…This dimer structure switches from parallel to anti-parallel in the presence of Cu 2+ and this process is regulated with the occupied binding sites of Cu [ 140 ]. Moreover, the same scholars later demonstrated that the nanomolar content of Cu 2+ has no impact on peptide–peptide bonds of dityrosine-linked β-amyloid dimers [ 141 ]. Another study has shown that Cu 2+ ions binding results in structural variations in the β-amyloid dimers, causing oligomer-defining interactions, including N-terminal interaction in them [ 142 ].…”

Alzheimer’s disease: How metal ions define β-amyloid function

“…However, literature reports on the properties of these variants differ to some extent, a heterogeneity that is explained from the differences in protocols applied, in particular regarding the preparation of monomer Aβ, but also in terms of analytical methods applied [61]. [436]. Wild-type murine Aβ contains three different amino acids within the metal binding N-terminal:…”

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

“…In fact, many studies indicated that zinc homeostasis is an important factor for the prevention and treatment of AD. However, others indicated that zinc may stimulate Aβ aggregation causing more harmful in AD [70], [71]. These conflicting reports were explained by the fact that 1 mM dose of zinc may be harmful for AD patients as zinc may reinforce Aβ aggregation and result in an increase in the number or size of neuronal Aβ plaques while low zinc (50 μM) exerts protective effects against Aβ-40 induced toxicity [72].…”