title: The protective effects and underlying mechanism of an anti-oligomeric Aβ42 single-chain variable fragment antibody.
abstract: Oligomeric Aβ42 aggregates have been identified as one of the major neurotoxic components of Alzheimer's disease (AD). Immunotherapy targeted against these Aβ42 aggregates has been proposed as an appropriate therapeutic approach for the treatment of AD. Here, we report an anti-oligomeric Aβ42 single-chain variable fragment (scFv) antibody, named MO6, obtained from the human antibody library of a healthy donor. ScFv MO6 specifically recognized and bound to the oligomeric Aβ42 (Aβ42 oligomers and immature protofibrils; 18-37 kDa), and reduced their levels mainly by blocking their formation, although scFv MO6 also induced disaggregation of Aβ42 aggregates. More importantly, scFv MO6 ameliorated or attenuated Aβ42-induced cytotoxicity and increased cell viability by up to 33%. Furthermore, scFv MO6 efficiently passed through an in vitro blood-brain barrier (BBB) model with a delivery efficiency of 66% after 60 min post-administration. ScFv MO6 is a monovalent antibody with an affinity constant (KD) of 5.2×10(-6) M for Aβ42 oligomers. Molecular docking simulations of Aβ42 to scFv MO6 revealed that the approach and specific binding of scFv MO6 to oligomeric Aβ42 aggregates was achieved by conformational recognition and directed induction, which resulted in a more dynamic adaptation of Aβ42 to scFv MO6, occurring mainly in the N-terminal (3-4), middle (12-19) and C-terminal (34-42) regions of Aβ42. This binding mode of scFv MO6 to Aβ42 explains its protective effects against oligomeric Aβ42. Our findings may be applied for the design of a smaller antibody specific for Aβ42 oligermers.
authors.affiliation: Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130012, PR China; Medical College, Qingdao University, Qingdao 266021, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130012, PR China.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Public Health, Jilin University, Changchun 130021, PR China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130012, PR China; School of Life Science, Jilin University, Changchun 130012, PR China. Electronic address: yingjiu@jlu.edu.cn.
authors.forename: Yingjiu
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D004353:Drug Evaluation, Preclinical; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D016415:Sequence Alignment; D057127:Single-Chain Antibodies / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D057127:Single-Chain Antibodies; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Aβ42 aggregate; Mechanism; Neurotoxicity; ScFv MO6 antibody