title: Copper inducing Aβ42 rather than Aβ40 nanoscale oligomer formation is the key process for Aβ neurotoxicity.
abstract: Copper is known to be a critical factor in Alzheimer's disease (AD) pathogenesis, as it is involved in amyloid-β (Aβ) peptide related toxicity. However, the relationship between neurotoxicity and Aβ peptide in the presence of copper remains unclear. The effect of copper has not been clearly differentiated between Aβ42 and Aβ40, and it is still debated whether copper-mediated neurotoxicity is due to reactive oxygen species (ROS) accumulation or other molecular mechanisms. Here, we describe that copper dramatically affects Aβ42 aggregation and enhances Aβ42 cytotoxicity while it shows no significant effects on Aβ40. These phenomena are mainly because that the strong interactions between copper and Aβ42 lead to great conformation changes, and stabilize Aβ42 aggregates at highly toxic nanoscale oligomer stage, whereas copper shows no similar impact on Aβ40. We also propose a possible molecular mechanism that copper enhances Aβ42 cytotoxicity via perturbing membrane structure. Moreover, we test the effect of an analogue of copper, nickel, on Aβ aggregation and cytotoxicity, finding that nickel also enhances cytotoxicity via Aβ42 nanoscale oligomer formation. These results clarify that the copper-induced Aβ42 nanoscale oligomer formation is the key process for Aβ neurotoxicity, and suggest that disrupting the interactions between copper and Aβ42 peptide to inhibit nanoscale oligomerization process, deserves more attention in AD drug development.
authors.affiliation: Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, 100084, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Jin
authors.forename: Wei-Hui
authors.initials: WH
authors.lastname: Wu
authors.forename: Qiu-Ye
authors.initials: QY
authors.lastname: Li
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Zhao
authors.forename: Yan-Mei
authors.initials: YM
authors.lastname: Li
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008422:Materials Testing; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D014025:Titanium / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009495:titanium dioxide; D003300:Copper; D014025:Titanium