Very small changes in the peptide sequence alter the redox properties of Aß(11-16)-Cu(II) and pAß(11-16)-Cu(II) ß-amyloid complexes

Alzheimer's disease is the most common neurodegenerative disease in the world and oxidative stress is a major factor in its pathogenesis. It is known that copper(II) ions forming complexes with peptides from the ss-amyloid (A ss) group can facilitate the production of reactive oxygen species. A very common amyloid in AD brain plaques A ss(11-42) form very stable Cu(II)-complexes that suppress ROS formation. However, when glutamic acid in A ss(11-42) undergoes dehydration form cyclic pyroglutamate, resulting in a new derivative pA ss(11-42), the Cu(II) stabilisation is much weaker. Here, we investigate, for the first time, the redox chemistry of pA ss(11-16)Cu (II) complexes as a model system for pA ss(11-42). We show that the weaker Cu(II) affinity for the pyroglutamate-modified peptide leads to Cu(I)/Cu(II) oxidation at potentials associated with increased ROS production. Our study also shows a significant difference in the redox properties of the complex if phosphate ions are present in the electrolyte, underlining the importance of proper choice of buffer solutions. These results can be crucial for an increased understanding of AD pathogenesis.

Automated summary

Alzheimer's disease is a neurodegenerative disease with oxidative stress as a major factor in its pathogenesis. Cu(II) ions complexed with Aβ peptides can facilitate the production of reactive oxygen species. Dehydration of glutamic acid in Aβ leads to weaker Cu(II) stabilization. The presence of phosphate ions in the electrolyte affects the redox properties of the complex.