The Co(II) ion binds to the N-terminal region of amyloid-beta (Aβ) peptides and modulates Aβ aggregation

Aggregating amyloid-β (Aβ) peptides play a central role in the neuropathology of Alzheimer’s disease (AD), the leading cause of dementia worldwide. In AD brains, Aβ peptides aggregate into insoluble amyloid plaques that contain elevated metal concentrations. AD patients furthermore often exhibit disrupted metal homeostasis. Despite extensive investigation, the metal aspect of AD remains unclear. Despite being an essential trace element with well-documented toxic properties, cobalt (Co) has received little attention in AD research. Here, we demonstrate for the first time that Co(II) ions bind to the N-terminal region of the biologically relevant full-length Aβ ₄₀ peptide. The His6, His13, and His14 residues participate in metal coordination. The binding affinity of the Co(II)·Aβ ₄₀ complex is relatively weak and estimated to around 0.3 mM. Thus, as expected, Aβ binding to Co(II) is weaker than to Cu(II), Ni(II), and Zn(II), but also weaker than Mn(II) binding, which is not consistent with the Irving–Williams series. Equimolar concentrations of Co(II) were found to disrupt normal Aβ40 fibrillation, primarily by interfering with fibril elongation. Co(II) also induced structural rearrangements—specifically coil–coil interactions—in Aβ ₄₀ monomers positioned in membrane-mimicking SDS micelles. These structural effects may influence the harmful Aβ aggregation processes underlying AD. More broadly, inducing protein misfolding and aggregation could be a general mechanism of cobalt toxicity.