Effect of Surface-Chelated Cu²⁺ on Amyloid-β Peptide Fibrillation

Abnormal interactions of copper (Cu) ions with amyloid-β (Aβ) peptides are believed to play an important role in the pathogenesis of Alzheimer's disease (AD). However, there is still debate as to the exact role of Cu ions in Aβ amyloidosis despite extensive studies on Aβ-Cu interactions. Unlike previously reported works, we herein study the effect of surface-chelated Cu²⁺, rather than the more usual solution-phase dissolved Cu²⁺, on Aβ aggregation. Through the combination of single molecule fluorescent tracking, atomic force microscopy imaging experiments, and all-atom molecular dynamic simulations, we show that the surface-chelated Cu²⁺ dynamically interacts with Aβ chains, restricts their 2D-diffusivity on the surface, and retards their fibrillation, while the designated surfaces without Cu²⁺ facilitate the 2D-diffusivity of Aβ chains for better interpeptide interaction and promote Aβ fibrillation. We offer a microscopic molecular insight into the retardation mechanism of surface-chelated Cu²⁺ on Aβ fibrillation, suggesting that the surface-bound pools of metal ions are critical in AD progression and drug design.