title: Human anti-Aβ IgGs target conformational epitopes on synthetic dimer assemblies and the AD brain-derived peptide.
abstract: Soluble non-fibrillar assemblies of amyloid-beta (Aβ) and aggregated tau protein are the proximate synaptotoxic species associated with Alzheimer's disease (AD). Anti-Aβ immunotherapy is a promising and advanced therapeutic strategy, but the precise Aβ species to target is not yet known. Previously, we and others have shown that natural human IgGs (NAbs) target diverse Aβ conformers and have therapeutic potential. We now demonstrate that these antibodies bound with nM avidity to conformational epitopes on plate-immobilized synthetic Aβ dimer assemblies, including synaptotoxic protofibrils, and targeted these conformers in solution. Importantly, NAbs also recognized Aβ extracted from the water-soluble phase of human AD brain, including species that migrated on denaturing PAGE as SDS-stable dimers. The critical reliance on Aβ's conformational state for NAb binding, and not a linear sequence epitope, was confirmed by the antibody's nM reactivity with plate-immobilized protofibrills, and weak uM binding to synthetic Aβ monomers and peptide fragments. The antibody's lack of reactivity against a linear sequence epitope was confirmed by our ability to isolate anti-Aβ NAbs from intravenous immunoglobulin using affinity matrices, immunoglobulin light chain fibrils and Cibacron blue, which had no sequence similarity with the peptide. These findings suggest that further investigations on the molecular basis and the therapeutic/diagnostic potential of anti-Aβ NAbs are warranted.
authors.affiliation: The Conway Institute, University College Dublin, Belfield, Dublin, Republic of Ireland.
authors.forename: Alfred T
authors.initials: AT
authors.lastname: Welzel
authors.forename: Angela D
authors.initials: AD
authors.lastname: Williams
authors.forename: Helen P
authors.initials: HP
authors.lastname: McWilliams-Koeppen
authors.forename: Luis
authors.initials: L
authors.lastname: Acero
authors.forename: Alfred
authors.initials: A
authors.lastname: Weber
authors.forename: Veronika
authors.initials: V
authors.lastname: Blinder
authors.forename: Alex
authors.initials: A
authors.lastname: Mably
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bunk
authors.forename: Corinna
authors.initials: C
authors.lastname: Hermann
authors.forename: Michael A
authors.initials: MA
authors.lastname: Farrell
authors.forename: Hartmut J
authors.initials: HJ
authors.lastname: Ehrlich
authors.forename: Hans P
authors.initials: HP
authors.lastname: Schwarz
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Alan
authors.initials: A
authors.lastname: Solomon
authors.forename: Brian
authors.initials: B
authors.lastname: O'Nuallain
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology; D052160:Benzothiazoles; D001703:Biophysics / Q000379:methods; D001921:Brain / Q000378:metabolism*; D002942:Circular Dichroism; D003704:Dementia / Q000378:metabolism; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D000939:Epitopes / Q000737:chemistry; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry; D016756:Immunoglobulins, Intravenous / Q000737:chemistry; D008854:Microscopy, Electron / Q000379:methods; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D000939:Epitopes; D007136:Immunoglobulins; D016756:Immunoglobulins, Intravenous; D010455:Peptides; D013844:Thiazoles; C009462:thioflavin T; D012967:Sodium Dodecyl Sulfate