title: An anti-Aβ (amyloid β) single-chain variable fragment prevents amyloid fibril formation and cytotoxicity by withdrawing Aβ oligomers from the amyloid pathway.
abstract: Aβ (amyloid β) immunotherapy has been revealed as a possible tool in Alzheimer's disease treatment. In contrast with complete antibodies, the administration of scFvs (single-chain variable fragments) produces neither meningoencephalitis nor cerebral haemorrhage. In the present study, the recombinant expression of scFv-h3D6, a derivative of an antibody specific for Aβ oligomers, is presented, as well as the subsequent proof of its capability to recover the toxicity induced by the Aβ1-42 peptide in the SH-SY5Y neuroblastoma cell line. To gain insight into the conformational changes underlying the prevention of Aβ toxicity by this antibody fragment, the conformational landscape of scFv-h3D6 upon temperature perturbation is also described. Heating the native state does not lead to any extent of unfolding, but rather directly to a β-rich intermediate state which initiates an aggregation pathway. This aggregation pathway is not an amyloid fibril pathway, as is that followed by the Aβ peptide, but rather a worm-like fibril pathway which, noticeably, turns out to be non-toxic. On the other hand, this pathway is thermodynamically and kinetically favoured when the scFv-h3D6 and Aβ1-42 oligomers form a complex in native conditions, explaining how the scFv-h3D6 withdraws Aβ1-42 oligomers from the amyloid pathway. To our knowledge, this is the first description of a conformational mechanism by which a scFv prevents Aβ-oligomer cytotoxicity.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Marín-Argany
authors.forename: Geovanny
authors.initials: G
authors.lastname: Rivera-Hernández
authors.forename: Joaquim
authors.initials: J
authors.lastname: Martí
authors.forename: Sandra
authors.initials: S
authors.lastname: Villegas
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology / Q000633:toxicity*; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D017510:Protein Folding; D057127:Single-Chain Antibodies / Q000737:chemistry* / Q000378:metabolism; D013696:Temperature
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D057127:Single-Chain Antibodies