Cu(II) Mediates Kinetically Distinct, Non-amyloidogenic Aggregation of Amyloid-β Peptides

Cu(II) ions are implicated in the pathogenesis of Alzheimer disease by influencing the aggregation of the amyloid-beta (A beta) peptide. Elucidating the underlying Cu(II)-inducedA beta aggregation is paramount for understanding the role of Cu(II) in the pathology of Alzheimer disease. The aim of this study was to characterize the qualitative and quantitative influence of Cu(II) on the extracellular aggregation mechanism and aggregate morphology of A beta(1-40) using spectroscopic, microelectrophoretic, mass spectrometric, and ultrastructural techniques. We found that the Cu(II):A beta ratio in solution has a major influence on (i) the aggregation kinetics/mechanism of A beta, because three different kinetic scenarios were observed depending on the Cu(II):A beta ratio, (ii) the metal: peptide stoichiometry in the aggregates, which increased to 1.4 at supra-equimolar Cu(II):A beta ratio; and (iii) the morphology of the aggregates, which shifted from fibrillar to non-fibrillar at increasing Cu(II):A beta ratios. We observed dynamic morphological changes of the aggregates, and that the formation of spherical aggregates appeared to be a common morphological end point independent on the Cu(II) concentration. Experiments with A beta(1-42) were compatible with the conclusions for A beta(1-40) even though the low solubility of A beta(1-42) precluded examination under the same conditions as for the A beta(1-40). Experiments with A beta(1-16) and A beta(1-28) showed that other parts than the Cu(II)-binding His residues were important for Cu(II)-induced A beta aggregation. Based on this study we propose three mechanistic models for the Cu(II)-induced aggregation of A beta(1-40) depending on the Cu(II):A beta ratio, and identify key reaction steps that may be feasible targets for preventing Cu(II)-associated aggregation or toxicity in Alzheimer disease.