title: Conformation-dependent scFv antibodies specifically recognize the oligomers assembled from various amyloids and show colocalization of amyloid fibrils with oligomers in patients with amyloidoses.
abstract: Increasing evidence indicates that amyloid aggregates, including oligomers, protofibrils or fibrils, are pivotal toxins in the pathogenesis of many amyloidoses such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, prion-related diseases, type 2 diabetes and hereditary renal amyloidosis. Various oligomers assembled from different amyloid proteins share common structures and epitopes. Here we present data indicating that two oligomer-specific single chain variable fragment (scFv) antibodies isolated from a naïve human scFv library could conformation-dependently recognize oligomers assembled from α-synuclein, amylin, insulin, Aβ1-40, prion peptide 106-126 and lysozyme, and fibrils from lysozyme. Further investigation showed that both scFvs inhibited the fibrillization of α-synuclein, amylin, insulin, Aβ1-40 and prion peptide 106-126, and disaggregated their preformed fibrils. However, they both promoted the aggregation of lysozyme. Nevertheless, the two scFv antibodies could attenuate the cytotoxicity of all amyloids tested. Moreover, the scFvs recognized the amyloid oligomers in all types of plaques, Lewy bodies and amylin deposits in the brain tissues of AD and PD patients and the pancreas of type 2 diabetes patients respectively, and showed that most amyloid fibril deposits were colocalized with oligomers in the tissues. Such conformation-dependent scFv antibodies may have potential application in the investigation of aggregate structures, the mechanisms of aggregation and cytotoxicity of various amyloids, and in the development of diagnostic and therapeutic reagents for many amyloidoses.
authors: Tsinghua University School of Medicine, Beijing, China.
authors: Xi
authors: X
authors: Zhang
authors: Xiao-xia
authors: XX
authors: Sun
authors: Di
authors: D
authors: Xue
authors: Dong-ge
authors: DG
authors: Liu
authors: Xiao-yan
authors: XY
authors: Hu
authors: Min
authors: M
authors: Zhao
authors: Shi-gao
authors: SG
authors: Yang
authors: Yang
authors: Y
authors: Yang
authors: Yong-jing
authors: YJ
authors: Xia
authors: Ying
authors: Y
authors: Wang
authors: Rui-tian
authors: RT
authors: Liu
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D000937:Antigen-Antibody Reactions; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs / Q000276:immunology*; D055503:Protein Multimerization / Q000276:immunology; D057127:Single-Chain Antibodies / Q000276:immunology / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000682:Amyloid; D046912:Multiprotein Complexes; D057127:Single-Chain Antibodies