title: Fibrillar seeds alleviate amyloid-β cytotoxicity by omitting formation of higher-molecular-weight oligomers.
abstract: Amyloid-β (Aβ) peptides can exist in distinct forms including monomers, oligomers and fibrils, consisting of increased numbers of monomeric units. Among these, Aβ oligomers are implicated as the primary toxic species as pointed by multiple lines of evidence. It has been suggested that toxicity could be rendered by the soluble higher-molecular-weight (high-n) Aβ oligomers. Yet, the most culpable form in the pathogenesis of Alzheimer's disease (AD) remains elusive. Moreover, the potential interaction among the insoluble fibrils that have been excluded from the responsible aggregates in AD development, Aβ monomers and high-n oligomers is undetermined. Here, we report that insoluble Aβ fibrillar seeds can interact with Aβ monomers at the stoichiometry of 1:2 (namely, each Aβ molecule of seed can bind to two Aβ monomers at a time) facilitating the fibrillization by omitting the otherwise mandatory formation of the toxic high-n oligomers during the fibril maturation. As a result, the addition of exogenous Aβ fibrillar seeds is seen to rescue neuronal cells from Aβ cytotoxicity presumably exerted by high-n oligomers, suggesting an unexpected protective role of Aβ fibrillar seeds.
authors.affiliation: Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China; Institute of Chemical Defence, Beijing 102205, PR China.
authors.forename: Wei-hui
authors.initials: WH
authors.lastname: Wu
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.forename: Ji-sheng
authors.initials: JS
authors.lastname: Yu
authors.forename: De-sheng
authors.initials: DS
authors.lastname: Zhao
authors.forename: Ye-ping
authors.initials: YP
authors.lastname: Yu
authors.forename: Jun-jie
authors.initials: JJ
authors.lastname: Luo
authors.forename: Jia
authors.initials: J
authors.lastname: Hu
authors.forename: Zhi-wu
authors.initials: ZW
authors.lastname: Yu
authors.forename: Yu-fen
authors.initials: YF
authors.lastname: Zhao
authors.forename: Yan-mei
authors.initials: YM
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides
keywords: 3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyltetrazoliumbromide; AD; Aggregation; Alzheimer’s disease; Aβ; DMEM; DMSO; Dulbecco’s modified Eagle’s medium; FBS; FTIR; Fibril; Fourier transform infrared spectroscopy; ITC; MEM; MTT; Monomer; Oligomer; PBS; SDS-PAGE; SEC; TEM; ThT; Thioflavin T; dimethyl sulfoxide; fetal bovine serum; isothermal titration calorimetry; minimum essential media; phosphate buffered saline; size exclusion chromatography; sodium dodecyl sulfate polyacrylamide gel electrophoresis; transmission electron microscope; β-amyloid