The Aggregation Pattern of Aβ 1-40 is Altered by the Presence of N-Truncated Aβ 4-40 and/or Cu II in a Similar Way through Ionic Interactions

Alzheimer's disease (AD) is one of the most common of the multifactorial diseases and is characterized by a range of abnormal molecular processes, such as the accumulation of extracellular plaques containing the amyloid-β (Aβ) peptides and dyshomeostasis of copper in the brain. In this study, we have investigated the effect of Cu on the aggregation of Aβ and Aβ , representing the two most prevalent families of Aβ peptides, that is, the full length and N-truncated peptides. Both families are similarly abundant in healthy and AD brains. For either of the studied peptides, substoichiometric Cu concentrations accelerated aggregation, whereas superstoichiometric Cu inhibited fibril formation, likely by stabilizing the oligomers. The addition of either Aβ or substoichiometric Cu affected the aggregation profile of Aβ , by yielding shorter and thicker fibrils; amorphous aggregates were formed in the presence of a molar excess of Cu . The similarity of these two effects can be attributed to the increase in the positive charge on the Aβ N terminus, caused both by Cu complexation and N truncation at position 4. Our findings provide a better understanding of the biological Aβ aggregation process as these two Aβ species and Cu coexist and interact under physiological conditions.