Oxidative Damages on the Alzheimer's Related-A beta Peptide Alters Its Ability to Assemble

Oxidative stress that can lead to oxidation of the amyloid-beta (A beta) peptide is considered a key feature in Alzheimer's disease (AD), influencing the ability of A beta to assemble into beta-sheet rich fibrils that are commonly found in senile plaques of AD patients. The present study aims at investigating the fallouts of A beta oxidation on the assembly properties of the A beta peptide. To accomplish this, we performed kinetics and analysis on an oxidized A beta ((ox)A beta) peptide, resulting from the attack of reactive oxygen species (ROS) that are formed by the biologically relevant Cu/A beta/dioxygen/ascorbate system. (ox)A beta was still able to assemble but displayed ill-defined and small oligomeric assemblies compared to the long and thick beta-sheet rich fibrils from the non-oxidized counterpart. In addition, (ox)A beta does affect the assembly of the parent A beta peptide. In a mixture of the two peptides, (ox)A beta has a mainly kinetic effect on the assembly of the A beta peptide and was able to slow down the formation of A beta fibril in a wide pH range [6.0-7.4]. However, (ox)A beta does not change the quantity and morphology of the A beta fibrils formed to a significant extent. In the presence of copper or zinc di-cations, (ox)A beta assembled into weakly-structured aggregates rather than short, untangled Cu-A beta fibrils and long untangled Zn-A beta fibrils. The delaying effect of (ox)A beta on metal altered A beta assembly was also observed. Hence, our results obtained here bring new insights regarding the tight interconnection between (i) ROS production leading to A beta oxidation and (ii) A beta assembly, in particular via the modulation of the A beta assembly by (ox)A beta. It is the first time that co-assembly of (ox)A beta and A beta under various environmental conditions (pH, metal ions horizontal ellipsis ) are reported.