title: Key roles of Tyr 10 in Cu bound Aβ complexes and its relevance to Alzheimer's disease.
abstract: 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.
authors.affiliation: Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China. Electronic address: naihaolu@jxnu.edu.cn.
authors.forename: Naihao
authors.initials: N
authors.lastname: Lu
authors.affiliation: Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China. Electronic address: zhgao144@mail.hust.edu.cn.
authors.forename: Zhonghong
authors.initials: Z
authors.lastname: Gao
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D009195:Peroxidase / Q000737:chemistry* / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D014443:Tyrosine; D003300:Copper; D009195:Peroxidase
keywords: Aβ aggregation; Aβ–Cu(II) complex; Neurochemistry; Oxidation; Tyrosine