title: Nitration of Tyrosine Residue Y10 of Aβ1-42Significantly Inhibits Its Aggregation and Cytotoxicity.
abstract: Amyloid-β plaques and oxidative stress are the major hallmarks of Alzheimer's disease. Our previous study found that the heme-Aβ complex enhanced the catalytic effect of free heme on protein tyrosine nitration in the presence of hydrogen peroxide (H2O2) and nitrite (NO2-). Y10 in Aβ could be the first target to be nitrated. We also found that nitration of Aβ1-40significantly decreased its aggregation. However, a contrary report showed that nitration of Aβ1-42by peroxynitrite enhanced its aggregation. To rule out the interference of peroxynitrite caused Aβ oxidation, we used synthetic Y10 nitrated Aβ1-42to study the influence of Y10 nitration on Aβ1-42's aggregation and cytotoxicity in this study. We confirmed that Aβ1-42could be nitrated in the presence of H2O2, NO2-, and heme by dot blotting. CD spectroscopy showed an increase of β-sheet structure of Aβ1-42and its mutants. The thioflavin T (ThT) flourescence assay revealed that both nitration and chlorination significantly inhibited Aβ1-42fibril formation. TEM and AFM observations of Aβ peptide aggregates further confirmed that Y10 modification inhibited Aβ1-42fibril formation. The cytotoxicity study of native and modified Aβ peptides on SH-SY5Y cells revealed that nitration of Aβ1-42remarkably decreased the neurotoxicity of Aβ1-42. On the basis of these results, we hypothesized that nitration of Y10 may block the π-π stacking interactions of Aβ1-42so that it inhibit its aggregation and neurotoxicity. More importantly, considerable evidence suggested that the levels of nitrite plus nitrate significantly decreased in the brain of AD patients. Thus, we believe that these findings would be helpful for further understanding the function of Aβ in AD.
authors.affiliation: School of Chemistry and Chemical Engineering, Hua Zhong University of Science and Technology , Wuhan 430074, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: School of Chemistry and Chemical Engineering, Hua Zhong University of Science and Technology , Wuhan 430074, People's Republic of China.
authors.forename: Jinming
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Houston , Houston, Texas 77004, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: School of Chemistry and Chemical Engineering, Hua Zhong University of Science and Technology , Wuhan 430074, People's Republic of China.|Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica , Wuhan, 430074, People's Republic of China.
authors.forename: Hailing
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Chemistry and Chemical Engineering, Hua Zhong University of Science and Technology , Wuhan 430074, People's Republic of China.|Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica , Wuhan, 430074, People's Republic of China.
authors.forename: Zhonghong
authors.identifier: 0000-0002-7878-9801
authors.initials: Z
authors.lastname: Gao
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D009573:Nitrites / Q000737:chemistry*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D030421:Peroxynitrous Acid / Q000737:chemistry; D066329:Protein Aggregates / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D014443:Tyrosine / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D009573:Nitrites; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D030421:Peroxynitrous Acid; D014443:Tyrosine; D006861:Hydrogen Peroxide