title: Monoclonal antibodies against Aβ42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain.
abstract: Amyloidogenic proteins generally form intermolecularly hydrogen-bonded β-sheet aggregates, including parallel, in-register β-sheets (recognized by antiserum OC) or antiparallel β-sheets, β-solenoids, β-barrels, and β-cylindrins (recognized by antiserum A11). Although these groups share many common properties, some amyloid sequences have been reported to form polymorphic structural variants or strains. We investigated the humoral immune response to Aβ42 fibrils and produced 23 OC-type monoclonal antibodies recognizing distinct epitopes differentially associated with polymorphic structural variants. These mOC antibodies define at least 18 different immunological profiles represented in aggregates of amyloid-β (Aβ). All of the antibodies strongly prefer amyloid aggregates over monomer, indicating that they recognize conformational epitopes. Most of the antibodies react with N-terminal linear segments of Aβ, although many recognize a discontinuous epitope consisting of an N-terminal domain and a central domain. Several of the antibodies that recognize linear Aβ segments also react with fibrils formed from unrelated amyloid sequences, indicating that reactivity with linear segments of Aβ does not mean the antibody is sequence-specific. The antibodies display strikingly different patterns of immunoreactivity in Alzheimer disease and transgenic mouse brain and identify spatially and temporally unique amyloid deposits. Our results indicate that the immune response to Aβ42 fibrils is diverse and reflects the structural polymorphisms in fibrillar amyloid structures. These polymorphisms may contribute to differences in toxicity and consequent effects on pathological processes. Thus, a single therapeutic monoclonal antibody may not be able to target all of the pathological aggregates necessary to make an impact on the overall disease process.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California 92697-3900 and.
authors.forename: Asa
authors.initials: A
authors.lastname: Hatami
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California 92697-3900 and.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Albay
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California 92697-3900 and.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Monjazeb
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California 92697-3900 and.
authors.forename: Saskia
authors.initials: S
authors.lastname: Milton
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California 92697-3900 and; Biochemistry Department, Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, 21589 Jeddah, Saudi Arabia. Electronic address: cglabe@uci.edu.
authors.forename: Charles
authors.initials: C
authors.lastname: Glabe
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001921:Brain / Q000276:immunology / Q000378:metabolism; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry; D006358:Hot Temperature; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D058225:Plaque, Amyloid / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D051844:alpha-Synuclein / Q000737:chemistry
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D000939:Epitopes; D010446:Peptide Fragments; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer Disease; Amyloid; Aβ; Monoclonal Antibody; Peptide Conformation; Protein Aggregation