Molecular Structure of Cu(II)-Bound Amyloid‑β Monomer Implicated in Inhibition of Peptide Self-Assembly in Alzheimer’s Disease

• Published in: JACS Au 2022-11, Vol.2 (11), p.2571-2584
• Main Authors: Abelein, Axel, Ciofi-Baffoni, Simone, Mörman, Cecilia, Kumar, Rakesh, Giachetti, Andrea, Piccioli, Mario, Biverstål, Henrik
• Format: Article
• Language: English
• Subjects: aggregation kinetics; Alzheimer’s disease; amyloid-β peptide; copper ion; Medicin och hälsovetenskap; paramagnetic NMR
• ISSN: 2691-3704; 2691-3704
• DOI: 10.1021/jacsau.2c00438

Metal ions, such as copper and zinc ions, have been shown to strongly modulate the self-assembly of the amyloid-β (Aβ) peptide into insoluble fibrils, and elevated concentrations of metal ions have been found in amyloid plaques of Alzheimer’s patients. Among the physiological transition metal ions, Cu­(II) ions play an outstanding role since they can trigger production of neurotoxic reactive oxygen species. In contrast, structural insights into Cu­(II) coordination of Aβ have been challenging due to the paramagnetic nature of Cu­(II). Here, we employed specifically tailored paramagnetic NMR experiments to determine NMR structures of Cu­(II) bound to monomeric Aβ. We found that monomeric Aβ binds Cu­(II) in the N-terminus and combined with molecular dynamics simulations, we could identify two prevalent coordination modes of Cu­(II). For these, we report here the NMR structures of the Cu­(II)–bound Aβ complex, exhibiting heavy backbone RMSD values of 1.9 and 2.1 Å, respectively. Further, applying aggregation kinetics assays, we identified the specific effect of Cu­(II) binding on the Aβ nucleation process. Our results show that Cu­(II) efficiently retards Aβ fibrillization by predominately reducing the rate of fibril-end elongation at substoichiometric ratios. A detailed kinetic analysis suggests that this specific effect results in enhanced Aβ oligomer generation promoted by Cu­(II). These results can quantitatively be understood by Cu­(II) interaction with the Aβ monomer, forming an aggregation inert complex. In fact, this mechanism is strikingly similar to other transition metal ions, suggesting a common mechanism of action of retarding Aβ self-assembly, where the metal ion binding to monomeric Aβ is a key determinant.