title: A mimotope peptide of Aβ42 fibril-specific antibodies with Aβ42 fibrillation inhibitory activity induces anti-Aβ42 conformer antibody response by a displayed form on an M13 phage in mice.
abstract: In Alzheimer's disease (AD), amyloid-β (Aβ) peptides accumulate in the brain in different forms, including fibrils and oligomers. Recently, we established three distinct conformation-dependent human single-chain Fv (scFv) antibodies, including B6 scFv, which bound to Aβ42 fibril but not to soluble-form Aβ, inhibiting Aβ42 fibril formation. In this study, we determined the mimotopes of these antibodies and found a common mimotope sequence, B6-C15, using the Ph.D.-C7C phage library. The B6-C15 showed weak homology to the C-terminus of Aβ42 containing GXXXG dimerization motifs. We synthesized the peptide of B6-C15 fused with biotinylated TAT at the N-terminus (TAT-B6-C15) and characterized its biochemical features on an Aβ42-fibrillation reaction in vitro. We demonstrated that, first, TAT-B6-C15 inhibited Aβ42 fibril formation; secondly, TAT-B6-C15 bound to prefibril Aβ42 oligomers but not to monomers, trimers, tetramers, fibrils, or ultrasonicated fragments; thirdly, TAT-B6-C15 inhibited Aβ42-induced cytotoxicity against human SH-SY5Y neuroblastoma cells; and, fourthly, when mice were administered B6-C15-phages dissolved in phosphate-buffered saline, the anti-Aβ42 conformer IgG antibody response was induced. These results suggested that the B6-C15 peptide might provide unique opportunities to analyze the Aβ42 fibrillation pathway and develop a vaccine vehicle for Alzheimer's disease.
authors.affiliation: Department of Chemistry, Biotechnology and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, Kagoshima 890-0065, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Shuhei
authors.initials: S
authors.lastname: Hashiguchi
authors.forename: Sho
authors.initials: S
authors.lastname: Takiguchi
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Haruna
authors.initials: H
authors.lastname: Tahara
authors.forename: Takuma
authors.initials: T
authors.lastname: Gotanda
authors.forename: Risa
authors.initials: R
authors.lastname: Abe
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ito
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Sugimura
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000918:Antibody Specificity; D017104:Bacteriophage M13 / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000276:immunology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D011487:Protein Conformation; D057127:Single-Chain Antibodies / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D007074:Immunoglobulin G; D010446:Peptide Fragments; D057127:Single-Chain Antibodies; C075222:amyloid beta-protein (1-42)