Key roles of Tyr 10 in Cu bound Aβ complexes and its relevance to Alzheimer's disease

• Aβ40–Cu(II) complex showed obviously enhanced peroxidase activity than free Cu(II).
• Aβ–Cu(II) complex caused oxidation and nitration of Tyr 10 under oxidative stress.
• Cu(I) and OH was formed as a chemical mechanism in peroxidase-like reaction.
• Tyr 10 residue was pivotal in Aβ aggregation and Aβ–Cu(II) complex.
• Cu(II) bound Aβ aggregates could retain peroxidase-like activity.

Recent studies show that the accumulation of redox-active Cu mediates the aggregation of amyloid β-peptide (Aβ) and conspicuous oxidative damage to the brain in Alzheimer's disease (AD). However, the key roles for Tyr 10 in Aβ–Cu(II) complex and its potential biological relevance to AD etiology under oxidative stress, were not stressed enough. Interestingly, our results indicated that Aβ40 (not Aβ16)–Cu(II) complex showed obviously enhanced peroxidase activity than free Cu(II). Although Tyr 10 was not the residue binding Cu(II), the mutation of Tyr 10 residue in Aβ40 decreased the peroxidase activity of Aβ40–Cu(II) complex, and the mutation of Tyr 10 could inhibit Aβ40 aggregation. Under oxidative and nitrative stress conditions, the Aβ–Cu(II) complex caused oxidation and nitration of the Aβ Tyr 10 residue through peroxidase-like reactions, where the formation of Cu(I) and hydroxyl radical (OH) was proposed as a chemical mechanism. We also showed that, when Aβ40 aggregates were bound to Cu(II), they retained peroxidase-like activity. Therefore, Tyr 10 residue is pivotal in Aβ–Cu(II) complex and shows important relevance to oxidative stress, implicating the novel significance of Tyr 10 residue as well as Aβ–Cu(II) complex in the pathology of AD.