title: A cyclic undecamer peptide mimics a turn in folded Alzheimer amyloid β and elicits antibodies against oligomeric and fibrillar amyloid and plaques.
abstract: The 39- to 42-residue amyloid β (Aβ) peptide is deposited in extracellular fibrillar plaques in the brain of patients suffering from Alzheimer's Disease (AD). Vaccination with these peptides seems to be a promising approach to reduce the plaque load but results in a dominant antibody response directed against the N-terminus. Antibodies against the N-terminus will capture Aβ immediately after normal physiological processing of the amyloid precursor protein and therefore will also reduce the levels of non-misfolded Aβ, which might have a physiologically relevant function. Therefore, we have targeted an immune response on a conformational neo-epitope in misfolded amyloid that is formed in advance of Aβ-aggregation. A tetanus toxoid-conjugate of the 11-meric cyclic peptide Aβ(22-28)-YNGK' elicited specific antibodies in Balb/c mice. These antibodies bound strongly to the homologous cyclic peptide-bovine serum albumin conjugate, but not to the homologous linear peptide-conjugate, as detected in vitro by enzyme-linked immunosorbent assay. The antibodies also bound--although more weakly--to Aβ(1-42) oligomers as well as fibrils in this assay. Finally, the antibodies recognized Aβ deposits in AD mouse and human brain tissue as established by immunohistological staining. We propose that the cyclic peptide conjugate might provide a lead towards a vaccine that could be administered before the onset of AD symptoms. Further investigation of this hypothesis requires immunization of transgenic AD model mice.
authors.affiliation: Department of Vaccinology, Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Peter.Hoogerhout@rivm.nl
authors.forename: Peter
authors.initials: P
authors.lastname: Hoogerhout
authors.forename: Willem
authors.initials: W
authors.lastname: Kamphuis
authors.forename: Humphrey F
authors.initials: HF
authors.lastname: Brugghe
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Sluijs
authors.forename: Hans A M
authors.initials: HA
authors.lastname: Timmermans
authors.forename: Janny
authors.initials: J
authors.lastname: Westdijk
authors.forename: Gijsbert
authors.initials: G
authors.lastname: Zomer
authors.forename: Claire J P
authors.initials: CJ
authors.lastname: Boog
authors.forename: Elly M
authors.initials: EM
authors.lastname: Hol
authors.forename: Germie P J M
authors.initials: GP
authors.lastname: van den Dobbelsteen
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000941:Antigens / Q000276:immunology; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007114:Immunization; D007150:Immunohistochemistry; D051379:Mice; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000276:immunology*; D058225:Plaque, Amyloid / Q000276:immunology*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D000941:Antigens; D010456:Peptides, Cyclic