Mechanistic approaches for chemically modifying the coordination sphere of copper–amyloid-β complexes
Jiyeon Han, Hyuck Jin Lee, Kyu Yeon Kim, Geewoo Nam, Junghyun Chae, Mi Hee Lim
Abstract
Significance Metal ions in the brain exhibit both functional (e.g., signal transduction, oxidative metabolism, and antioxidant defense) and pathological qualities (e.g., oxidative damage). Impaired metal ion homeostasis is linked to the decrease in enzymatic activities, the elevation of protein aggregation, and oxidative stress, leading to neurodegeneration. Particularly, copper coordinates to amyloid-β (Aβ) peptides, a pathological factor of Alzheimer’s disease, facilitating Aβ aggregation and inducing oxidative stress. Our work presents a mechanistic strategy to modify the coordination sphere of Cu(II) bound to Aβ using a chemical reagent by promoting copper–O 2 chemistry, which can inhibit Cu(II) binding to Aβ and alter Aβ’s aggregation and toxicity. Our multidisciplinary studies demonstrate a direction for modulating copper-interacting amyloidogenic proteins.