title: Central amyloid-β-specific single chain variable fragment ameliorates Aβ aggregation and neurotoxicity.
abstract: Anti-amyloid-β immunotherapies are a promising therapeutic approach for the treatment and prevention of Alzheimer's disease (AD). Single chain antibody fragments (scFv) are an attractive alternative to whole antibodies due to their small size, single polypeptide format and inability to stimulate potentially undesirable Fc-mediated immune effector functions. We have generated the scFv derivative of anti-Aβ monoclonal antibody, 1E8, known to target residues 17-22 of Aβ. Here we show that the soluble 1E8 scFv binds to the central region of Aβ with an affinity of ~55 nM and significantly reduces fibril formation of Aβ(1-42). Furthermore, 1E8 scFv ameliorates Aβ(1-42)-mediated toxicity in the PC12 cell line and murine primary neuronal cultures. This ability to both target the central region of Aβ and prevent Aβ(1-42) neurotoxicity in vitro makes it a promising therapeutic antibody building block for further functionalization, toward the treatment of AD.
authors.affiliation: Division of Materials Science and Engineering, CSIRO Preventative Health Flagship, 343 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: R M
authors.initials: RM
authors.lastname: Nisbet
authors.forename: J
authors.initials: J
authors.lastname: Nigro
authors.forename: K
authors.initials: K
authors.lastname: Breheney
authors.forename: J
authors.initials: J
authors.lastname: Caine
authors.forename: M K
authors.initials: MK
authors.lastname: Hattarki
authors.forename: S D
authors.initials: SD
authors.lastname: Nuttall
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology*; D000818:Animals; D000918:Antibody Specificity; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology*; D011247:Pregnancy; D015202:Protein Engineering; D055503:Protein Multimerization / Q000276:immunology*; D017433:Protein Structure, Secondary; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; amyloid-beta; immunotherapy; single chain antibody