Mechanistic approaches for chemically modifying the coordination sphere of copper–amyloid-β complexes

Abstract

Neurotoxic implications of the interactions between Cu(I/II) and amyloid-β (Aβ) indicate a connection between amyloid cascade hypothesis and metal ion hypothesis with respect to the neurodegeneration associated with Alzheimer’s disease (AD). Herein, we report a mechanistic strategy for modifying the first coordination sphere of Cu(II) bound to Aβ utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)–Aβ was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)–Aβ was able to disrupt binding of Cu(II) to Aβ and result in chemically modified Aβ with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)–Aβ could stem from the molecule’s ability to 1) interact with Cu(II)–Aβ and 2) foster copper–O2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)–Aβ at a metal-binding amino acid residue and consequently alter Aβ’s coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.

Amyloid-beta–copper interaction studied by simultaneous nitrogen K and copper L2,3-edge soft X-ray absorption spectroscopy

“…This is in agreement with a 1:1 reaction stoichiometric ratio of Cu(II) to Ab (Atria ´n-Blasco et al, 2017). The spectrum of the 1000 mM sample (incubated for 1 day at 30 C) has a slightly lower intensity of the p* peak and a different pre-peak feature that could originate from the structural changes because of the different aggregation pathway in the presence of the concentrated Cu(II) ions (Han et al, 2021;Mold et al, 2013;Viles, 2012). At a high stoichiometric ratio of Cu(II) to Ab, Cu(II) precipitates Ab 42 as amorphous deposits (Mold et al, 2013;Viles, 2012).…”

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for the Soluble Amyloid-β Oligomers in Alzheimer’s Disease

“…The triazamacrocycle moiety is known to act as a strong metal-chelating ligand, including binding to Cu 2+ ions. Since compound LS-4 should be mono-protonated under normal pH, [25][26][27][28][29][30] the Cu 2+ -LS-4 complex should also be monocationic like the monoprotonated LS-4, and could potentially exhibit similar amyloid binding properties as LS-4. As a result, we have employed the Cu-LS-4 complex to probe its fluorescence properties when interacting with the Aβ42oligomers and fibrils.…”

Redox signaling and Alzheimer’s disease: from pathomechanism insights to biomarker discovery and therapy strategy

“…2) [20]. The critical role of redox-active metals in AD pathogenesis strongly argued that amyloid-specific metal be exploited as possible therapeutic targets for this horrible disease [93]. Of note, although metal chelation is recognized as a promising therapy for AD treatment [94], the widespread clinical use of chelators remains a huge challenge as most chelators possess limited efficacy to differentiate toxic metals that tightly associated with Aβ plaques from those required by metal homeostasis [95].…”