The Aggregation Pattern of Aß1-40 is Altered by the Presence of N-Truncated Aß4-40 and/or CuII 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-ß (Aß) peptides and dyshomeostasis of copper in the brain. In this study, we have investigated the effect of CuII on the aggregation of Aß1-40 and Aß4-40 , representing the two most prevalent families of Aß 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 CuII concentrations accelerated aggregation, whereas superstoichiometric CuII inhibited fibril formation, likely by stabilizing the oligomers. The addition of either Aß4-40 or substoichiometric CuII affected the aggregation profile of Aß1-40 , by yielding shorter and thicker fibrils; amorphous aggregates were formed in the presence of a molar excess of CuII . The similarity of these two effects can be attributed to the increase in the positive charge on the Aß N terminus, caused both by CuII complexation and N truncation at position 4. Our findings provide a better understanding of the biological Aß aggregation process as these two Aß species and CuII coexist and interact under physiological conditions.