Human Anti-Aβ IgGs Target Conformational Epitopes on Synthetic Dimer Assemblies and the AD Brain-Derived Peptide
| Autor: | Hans Peter Schwarz, Alex Mably, Corinna Hermann, Alfred L. Weber, Brian O'Nuallain, Alfred T. Welzel, Angela Williams, Michael A. Farrell, Veronika Blinder, Alan Solomon, Sebastian Bunk, Hartmut J. Ehrlich, Helen P. McWilliams-Koeppen, Dominic M. Walsh, Luis Acero |
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| Rok vydání: | 2012 |
| Předmět: |
Protein Conformation
lcsh:Medicine Antigen Processing and Recognition Peptide Epitope Epitopes 0302 clinical medicine Protein structure Neurobiology of Disease and Regeneration lcsh:Science Immune Response chemistry.chemical_classification 0303 health sciences Multidisciplinary biology Circular Dichroism Brain Immunoglobulins Intravenous Sodium Dodecyl Sulfate Neurodegenerative Diseases Middle Aged 3. Good health Cerebellar Disorders Neurology Biochemistry Medicine Electrophoresis Polyacrylamide Gel Female Antibody Dimerization Research Article Immunoprecipitation Immunology Biophysics Immunoglobulins Immunoglobulin light chain 03 medical and health sciences Alzheimer Disease Humans Avidity Benzothiazoles Biology Aged 030304 developmental biology Amyloid beta-Peptides lcsh:R Microscopy Electron Thiazoles chemistry biology.protein lcsh:Q Clinical Immunology Dementia Linear Sequence Epitope Peptides 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 11, p e50317 (2012) PLoS ONE; Vol 7 |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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