title: 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.
authors.affiliation: Key Laboratory of Functional Small Organic Molecule, Ministry of Education and College of Life Science, ‡Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University , 99 Ziyang Road, Nanchang, Jiangxi 330022, China.
authors.forename: Naihao
authors.initials: N
authors.lastname: Lu
authors.forename: Jiayu
authors.initials: J
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Peng
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D006418:Heme / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress; D010544:Peroxidases / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D014443:Tyrosine; D006418:Heme; D010544:Peroxidases