The Aggregation Pattern of Aβ_1–40 is Altered by the Presence of <i>N</i>‐Truncated Aβ_4–40 and/or Cu^II in a Similar Way through Ionic Interactions

Abstract

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^II on the aggregation of Aβ_1-40 and Aβ_4-40 , 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^II concentrations accelerated aggregation, whereas superstoichiometric Cu^II inhibited fibril formation, likely by stabilizing the oligomers. The addition of either Aβ_4-40 or substoichiometric Cu^II affected the aggregation profile of Aβ_1-40 , by yielding shorter and thicker fibrils; amorphous aggregates were formed in the presence of a molar excess of Cu^II . 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^II 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^II coexist and interact under physiological conditions.