title: Aβ-40 Y10F increases βfibrils formation but attenuates the neurotoxicity of amyloid-β peptide.
abstract: Alzheimer's disease (AD) is characterized by the abnormal aggregation of amyloid-β peptide (Aβ) in extracellular deposits known as senile plaques. The tyrosine residue (Tyr-10) is believed to be important in Aβ-induced neurotoxicity due to the formation of tyrosyl radicals. To reduce the likelihood of cross-linking, here we designed an Aβ-40 analogue (Aβ-40 Y10F) in which the tyrosine residue was substituted by a structurally similar residue, phenylalanine. The aggregation rate was determined by the Thioflavin T (ThT) assay, in which Aβ-40 Y10F populated an ensemble of folded conformations much quicker and stronger than the wild type Aβ. Biophysical tests subsequently confirmed the results of the ThT assay, suggesting the measured increase of β-aggregation may arise predominantly from enhancement of hydrophobicity upon substitution and thus the propensity of intrinsic β-sheet formation. Nevertheless, Aβ-40 Y10F exhibited remarkably decreased neurotoxicity compared to Aβ-40 which could be partly due to the reduced generation of hydrogen peroxide. These findings may lead to further understanding of the structural perturbation of Aβ to its fibrillation.
authors: Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing 100191, China.|Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing 100191, China.
authors: Xueling
authors: X
authors: Dai
authors: Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing 100191, China.
authors: Ping
authors: P
authors: Chang
authors: Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing 100191, China.
authors: Wenjuan
authors: W
authors: Liu
authors: College of Life Science, Capital Normal University, Beijing 100048, China.
authors: Ke
authors: K
authors: Xu
authors: Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing 100191, China.
authors: Yaxuan
authors: Y
authors: Sun
authors: Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing 100191, China.
authors: Shigong
authors: S
authors: Zhu
authors: Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, Beijing 100191, China.
authors: Zhaofeng
authors: Z
authors: Jiang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D010649:Phenylalanine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D014443:Tyrosine; D010649:Phenylalanine; D006861:Hydrogen Peroxide