Key roles for tyrosine 10 in aβ-heme complexes and its relevance to oxidative stress.

Abstract

Amyloid β-peptide (Aβ) aggregation in the brain, known as amyloid plaques, is a pathological feature of Alzheimer's disease (AD). Recent studies show that heme binds to the His residue of Aβ with the iron center and subsequently forms an Aβ-heme complex, which can inhibit Aβ aggregation. Although Tyr-10 was not the residue binding heme, the key roles for Tyr-10 in Aβ-heme complexes and its potential biological relevance to AD etiology under oxidative stress were not sufficiently evaluated. Here, we used wild-type and Tyr-10-mutated human Aβ peptides and studied the impact of the mutation on Aβ-heme peroxidase activity, heme-bound Aβ aggregation, and oxidation and nitration under oxidative and nitrative stresses. Our results indicate that the mutation of Tyr-10 in Aβ16 and Aβ40 decreased the peroxidase activity of Aβ-heme complexes and that the mutation of Tyr-10 could inhibit Aβ40 self-assembly aggregation. Under oxidative (H2O2) and nitrative (H2O2/NaNO2) stress conditions, the Aβ40-heme complexes caused oxidation and nitration of the Aβ Tyr-10 residue through promoting peroxidase-like reactions, which were different from the classic inhibitive effect of heme on Aβ aggregation. To our knowledge, this is the first time that the formation of a heme-to-protein cross-linked Aβ40-heme complex under oxidative stress has been reported; in addition, the mutation of Tyr-10 could inhibit the cross-link formation. Therefore, Tyr-10 is pivotal in Aβ-heme complexes and plays key roles in Aβ aggregation under oxidative and nitrative stresses, demonstrating a novel significance of Tyr-10 as well as Aβ-heme complexes in the pathology of AD.