High Resolution Image Download MS PowerPoint Slide Alzheimer’s disease is linked to the formation and accumulation of extracellular β-amyloid aggregates, with toxicity primarily attributed to soluble oligomeric species, as proposed by the oligomeric hypothesis. Concurrently, the metal ion hypothesis suggests that transition metal ions, such as Cu 2+ and Zn 2+, directly modulate the aggregation process and the structural stability of β-amyloid (Aβ) fragments. In this study, molecular dynamics simulations were employed to produce collective variables to investigate the effects of these ions and their concentrations on the aggregation of the β-amyloid 1–16 and 25–35 fragments in aqueous solution for the first time. The free energy profile of aggregation indicates that the presence of Cu 2+ ions slightly decreases the energy associated with the aggregation of the β-amyloid 1–16 fragment, suggesting it acts as a modulator that partially stabilizes the oligomers. In contrast, we report for the first time that Zn 2+ ions do not reduce the energy barrier for the aggregation of the β-amyloid 1–16 fragment in aqueous solution. Zn 2+ displays a higher affinity for the acidic residues of Aβ 1–16, establishing more frequent, yet less selective, contacts compared to those observed for Cu 2+ ions. The main finding is that Cu 2+ and Zn 2+ ions modulate the early aggregation pathway of β-amyloid. In particular, at high concentrations, Cu 2+ favors the formation of small, structurally ordered proto-oligomers enriched in antiparallel β-sheets, rather than simply increasing aggregate size, whereas Zn 2+ does not exhibit an analogous effect under the conditions studied. This metal-induced stabilization of β-sheet-rich low-order oligomers, particularly pronounced for Cu 2+, identifies early secondary structure transitions as the primary determinant of amyloid toxicity and a critical molecular event in Alzheimer’s disease. The evidence presented in this study enhances our understanding of the oligomeric and metal ion hypotheses of Alzheimer’s disease.
Costa et al. (Mon,) studied this question.