Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies.
The self-assembly of Aβ peptides into a range of conformationally heterogeneous amyloid states represents a fundamental event in Alzheimer's disease. Within these structures oligomeric intermediates are considered to be particularly pathogenic. To test this hypothesis we have used a conformatio...
Published in: | Acta Neuropathologica Communications |
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Biomed Central
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ftdznevdb:oai:pub.dzne.de:139733 2023-10-09T21:49:32+02:00 Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies. Wacker, Jessica Rönicke, Raik Westermann, Martin Wulff, Melanie Reymann, Klaus G Dobson, Christopher M Horn, Uwe Crowther, Damian C Luheshi, Leila M Fändrich, Marcus DE 2014 https://pub.dzne.de/record/139733 https://pub.dzne.de/search?p=id:%22DZNE-2020-06055%22 eng eng Biomed Central info:eu-repo/semantics/altIdentifier/issn/2051-5960 info:eu-repo/semantics/altIdentifier/pmid/pmid:24725347 info:eu-repo/semantics/altIdentifier/doi/10.1186/2051-5960-2-43 https://pub.dzne.de/record/139733 https://pub.dzne.de/search?p=id:%22DZNE-2020-06055%22 info:eu-repo/semantics/closedAccess Acta Neuropathologica Communications 2(1), 43 (2014). doi:10.1186/2051-5960-2-43 info:eu-repo/classification/ddc/610 Amino Acid Sequence Amyloid beta-Peptides: genetics Amyloid beta-Peptides: immunology Amyloid beta-Peptides: metabolism Amyloid beta-Peptides: pharmacology Animals Genetically Modified Antibodies: chemistry Antibodies: genetics Antibodies: pharmacology Antibodies: therapeutic use Cell Line Tumor Disease Models Animal Drosophila Proteins: genetics Drosophila melanogaster Eye: metabolism Eye: ultrastructure Hippocampus: drug effects Hippocampus: physiology Humans Long-Term Potentiation: drug effects Long-Term Potentiation: genetics Mice Inbred C57BL Neuroblastoma: pathology Neurotoxicity Syndromes: drug therapy Neurotoxicity Syndromes: etiology Neurotoxicity Syndromes: physiopathology Peptide Fragments: genetics Peptide Fragments: immunology Peptide Fragments: metabolism Peptide Fragments: pharmacology Protein Aggregation Pathological Protein Binding: drug effects Protein Conformation Amyloid beta-Peptides Antibodies Drosophila Proteins Peptide Fragments amyloid beta-protein (1-40) amyloid beta-protein (1-42) info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 2014 ftdznevdb https://doi.org/10.1186/2051-5960-2-43 2023-09-21T07:35:32Z The self-assembly of Aβ peptides into a range of conformationally heterogeneous amyloid states represents a fundamental event in Alzheimer's disease. Within these structures oligomeric intermediates are considered to be particularly pathogenic. To test this hypothesis we have used a conformational targeting approach where particular conformational states, such as oligomers or fibrils, are recognized in vivo by state-specific antibody fragments.We show that oligomer targeting with the KW1 antibody fragment, but not fibril targeting with the B10 antibody fragment, affects toxicity in Aβ-expressing Drosophila melanogaster. The effect of KW1 is observed to occur selectively with flies expressing Aβ(1-40) and not with those expressing Aβ(1-42) or the arctic variant of Aβ(1-42) This finding is consistent with the binding preference of KW1 for Aβ(1-40) oligomers that has been established in vitro. Strikingly, and in contrast to the previously demonstrated in vitro ability of this antibody fragment to block oligomeric toxicity in long-term potentiation measurements, KW1 promotes toxicity in the flies rather than preventing it. This result shows the crucial importance of the environment in determining the influence of antibody binding on the nature and consequences of the protein misfolding and aggregation.While our data support to the pathological relevance of oligomers, they highlight the issues to be addressed when developing inhibitory strategies that aim to neutralize these states by means of antagonistic binding agents. Article in Journal/Newspaper Arctic DZNEPUB (German Center for Neurodegenerative Diseases) Arctic Acta Neuropathologica Communications 2 1 |
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DZNEPUB (German Center for Neurodegenerative Diseases) |
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language |
English |
topic |
info:eu-repo/classification/ddc/610 Amino Acid Sequence Amyloid beta-Peptides: genetics Amyloid beta-Peptides: immunology Amyloid beta-Peptides: metabolism Amyloid beta-Peptides: pharmacology Animals Genetically Modified Antibodies: chemistry Antibodies: genetics Antibodies: pharmacology Antibodies: therapeutic use Cell Line Tumor Disease Models Animal Drosophila Proteins: genetics Drosophila melanogaster Eye: metabolism Eye: ultrastructure Hippocampus: drug effects Hippocampus: physiology Humans Long-Term Potentiation: drug effects Long-Term Potentiation: genetics Mice Inbred C57BL Neuroblastoma: pathology Neurotoxicity Syndromes: drug therapy Neurotoxicity Syndromes: etiology Neurotoxicity Syndromes: physiopathology Peptide Fragments: genetics Peptide Fragments: immunology Peptide Fragments: metabolism Peptide Fragments: pharmacology Protein Aggregation Pathological Protein Binding: drug effects Protein Conformation Amyloid beta-Peptides Antibodies Drosophila Proteins Peptide Fragments amyloid beta-protein (1-40) amyloid beta-protein (1-42) |
spellingShingle |
info:eu-repo/classification/ddc/610 Amino Acid Sequence Amyloid beta-Peptides: genetics Amyloid beta-Peptides: immunology Amyloid beta-Peptides: metabolism Amyloid beta-Peptides: pharmacology Animals Genetically Modified Antibodies: chemistry Antibodies: genetics Antibodies: pharmacology Antibodies: therapeutic use Cell Line Tumor Disease Models Animal Drosophila Proteins: genetics Drosophila melanogaster Eye: metabolism Eye: ultrastructure Hippocampus: drug effects Hippocampus: physiology Humans Long-Term Potentiation: drug effects Long-Term Potentiation: genetics Mice Inbred C57BL Neuroblastoma: pathology Neurotoxicity Syndromes: drug therapy Neurotoxicity Syndromes: etiology Neurotoxicity Syndromes: physiopathology Peptide Fragments: genetics Peptide Fragments: immunology Peptide Fragments: metabolism Peptide Fragments: pharmacology Protein Aggregation Pathological Protein Binding: drug effects Protein Conformation Amyloid beta-Peptides Antibodies Drosophila Proteins Peptide Fragments amyloid beta-protein (1-40) amyloid beta-protein (1-42) Wacker, Jessica Rönicke, Raik Westermann, Martin Wulff, Melanie Reymann, Klaus G Dobson, Christopher M Horn, Uwe Crowther, Damian C Luheshi, Leila M Fändrich, Marcus Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies. |
topic_facet |
info:eu-repo/classification/ddc/610 Amino Acid Sequence Amyloid beta-Peptides: genetics Amyloid beta-Peptides: immunology Amyloid beta-Peptides: metabolism Amyloid beta-Peptides: pharmacology Animals Genetically Modified Antibodies: chemistry Antibodies: genetics Antibodies: pharmacology Antibodies: therapeutic use Cell Line Tumor Disease Models Animal Drosophila Proteins: genetics Drosophila melanogaster Eye: metabolism Eye: ultrastructure Hippocampus: drug effects Hippocampus: physiology Humans Long-Term Potentiation: drug effects Long-Term Potentiation: genetics Mice Inbred C57BL Neuroblastoma: pathology Neurotoxicity Syndromes: drug therapy Neurotoxicity Syndromes: etiology Neurotoxicity Syndromes: physiopathology Peptide Fragments: genetics Peptide Fragments: immunology Peptide Fragments: metabolism Peptide Fragments: pharmacology Protein Aggregation Pathological Protein Binding: drug effects Protein Conformation Amyloid beta-Peptides Antibodies Drosophila Proteins Peptide Fragments amyloid beta-protein (1-40) amyloid beta-protein (1-42) |
description |
The self-assembly of Aβ peptides into a range of conformationally heterogeneous amyloid states represents a fundamental event in Alzheimer's disease. Within these structures oligomeric intermediates are considered to be particularly pathogenic. To test this hypothesis we have used a conformational targeting approach where particular conformational states, such as oligomers or fibrils, are recognized in vivo by state-specific antibody fragments.We show that oligomer targeting with the KW1 antibody fragment, but not fibril targeting with the B10 antibody fragment, affects toxicity in Aβ-expressing Drosophila melanogaster. The effect of KW1 is observed to occur selectively with flies expressing Aβ(1-40) and not with those expressing Aβ(1-42) or the arctic variant of Aβ(1-42) This finding is consistent with the binding preference of KW1 for Aβ(1-40) oligomers that has been established in vitro. Strikingly, and in contrast to the previously demonstrated in vitro ability of this antibody fragment to block oligomeric toxicity in long-term potentiation measurements, KW1 promotes toxicity in the flies rather than preventing it. This result shows the crucial importance of the environment in determining the influence of antibody binding on the nature and consequences of the protein misfolding and aggregation.While our data support to the pathological relevance of oligomers, they highlight the issues to be addressed when developing inhibitory strategies that aim to neutralize these states by means of antagonistic binding agents. |
format |
Article in Journal/Newspaper |
author |
Wacker, Jessica Rönicke, Raik Westermann, Martin Wulff, Melanie Reymann, Klaus G Dobson, Christopher M Horn, Uwe Crowther, Damian C Luheshi, Leila M Fändrich, Marcus |
author_facet |
Wacker, Jessica Rönicke, Raik Westermann, Martin Wulff, Melanie Reymann, Klaus G Dobson, Christopher M Horn, Uwe Crowther, Damian C Luheshi, Leila M Fändrich, Marcus |
author_sort |
Wacker, Jessica |
title |
Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies. |
title_short |
Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies. |
title_full |
Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies. |
title_fullStr |
Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies. |
title_full_unstemmed |
Oligomer-targeting with a conformational antibody fragment promotes toxicity in Aβ-expressing flies. |
title_sort |
oligomer-targeting with a conformational antibody fragment promotes toxicity in aβ-expressing flies. |
publisher |
Biomed Central |
publishDate |
2014 |
url |
https://pub.dzne.de/record/139733 https://pub.dzne.de/search?p=id:%22DZNE-2020-06055%22 |
op_coverage |
DE |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Acta Neuropathologica Communications 2(1), 43 (2014). doi:10.1186/2051-5960-2-43 |
op_relation |
info:eu-repo/semantics/altIdentifier/issn/2051-5960 info:eu-repo/semantics/altIdentifier/pmid/pmid:24725347 info:eu-repo/semantics/altIdentifier/doi/10.1186/2051-5960-2-43 https://pub.dzne.de/record/139733 https://pub.dzne.de/search?p=id:%22DZNE-2020-06055%22 |
op_rights |
info:eu-repo/semantics/closedAccess |
op_doi |
https://doi.org/10.1186/2051-5960-2-43 |
container_title |
Acta Neuropathologica Communications |
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2 |
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1 |
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1779312561947148288 |