The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers
The amyloid beta-peptide (Aβ) plays a leading role in Alzheimer's disease (AD) physiopathology. Even though monomeric forms of Aβ are harmless to cells, Aβ can aggregate into β-sheet oligomers and fibrils, which are both neurotoxic. Therefore, one of the main therapeutic approaches to cure...
| Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | article |
| Status: | Published version |
| Publication Date: | 2017 |
| Country: | España |
| Institution: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repository: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/33732 |
| Online Access: | http://hdl.handle.net/10230/33732 http://dx.doi.org/10.18632/oncotarget.17074 |
| Access Level: | Open access |
| Keyword: | Alzheimer’s disease Amyloid Immunoglobulin Fab Oligomers |
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The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomersValls Comamala, Victòria, 1987-Guivernau Almazán, Biuse, 1988-Bonet Martínez, Jaume, 1982-Puig, MartaPerálvarez Marín, AlexPalomer, ErnestFernàndez Busquets, XavierAltafaj, XavierTajes Orduña, MartaPuig-Pijoan, AlbertVicente García, Rubén, 1978-Oliva Miguel, BaldomeroMuñoz López, Francisco José, 1964-Alzheimer’s diseaseAmyloidImmunoglobulinFabOligomersThe amyloid beta-peptide (Aβ) plays a leading role in Alzheimer's disease (AD) physiopathology. Even though monomeric forms of Aβ are harmless to cells, Aβ can aggregate into β-sheet oligomers and fibrils, which are both neurotoxic. Therefore, one of the main therapeutic approaches to cure or delay AD onset and progression is targeting Aβ aggregation. In the present study, we show that a pool of human gamma immunoglobulins (IgG) protected cortical neurons from the challenge with Aβ oligomers, as assayed by MTT reduction, caspase-3 activation and cytoskeleton integrity. In addition, we report the inhibitory effect of IgG on Aβ aggregation, as shown by Thioflavin T assay, size exclusion chromatography and atomic force microscopy. Similar results were obtained with Palivizumab, a human anti-sincitial virus antibody. In order to dissect the important domains, we cleaved the pool of human IgG with papain to obtain Fab and Fc fragments. Using these cleaved fragments, we functionally identified Fab as the immunoglobulin fragment inhibiting Aβ aggregation, a result that was further confirmed by an in silico structural model. Interestingly, bioinformatic tools show a highly conserved structure able to bind amyloid in the Fab region. Overall, our data strongly support the inhibitory effect of human IgG on Aβ aggregation and its neuroprotective role.This work was supported by the Plan Estatal de I+D+I 2013-2016 and the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Grants PI13/00408, PI13/00135, and Miguel Servet Grant CP10/00548 to X.A.) and FEDER Funds; SAF2014-52228-R; BIO2014-57518-R and Fundació La Marató-TV3 (Nº 20140210; Nº 20134030)Impact Journals201820182017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/33732http://dx.doi.org/10.18632/oncotarget.17074reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésOncotarget. 2017 Jun 20;8(25):41154-65info:eu-repo/grantAgreement/ES/1PE/SAF2014-52228-Rinfo:eu-repo/grantAgreement/ES/1PE/BIO2014-57518-RValls-Comamala et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY) (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.http://creativecommons.org/licenses/by/3.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/337322026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers |
| title |
The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers |
| spellingShingle |
The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers Valls Comamala, Victòria, 1987- Alzheimer’s disease Amyloid Immunoglobulin Fab Oligomers |
| title_short |
The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers |
| title_full |
The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers |
| title_fullStr |
The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers |
| title_full_unstemmed |
The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers |
| title_sort |
The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers |
| dc.creator.none.fl_str_mv |
Valls Comamala, Victòria, 1987- Guivernau Almazán, Biuse, 1988- Bonet Martínez, Jaume, 1982- Puig, Marta Perálvarez Marín, Alex Palomer, Ernest Fernàndez Busquets, Xavier Altafaj, Xavier Tajes Orduña, Marta Puig-Pijoan, Albert Vicente García, Rubén, 1978- Oliva Miguel, Baldomero Muñoz López, Francisco José, 1964- |
| author |
Valls Comamala, Victòria, 1987- |
| author_facet |
Valls Comamala, Victòria, 1987- Guivernau Almazán, Biuse, 1988- Bonet Martínez, Jaume, 1982- Puig, Marta Perálvarez Marín, Alex Palomer, Ernest Fernàndez Busquets, Xavier Altafaj, Xavier Tajes Orduña, Marta Puig-Pijoan, Albert Vicente García, Rubén, 1978- Oliva Miguel, Baldomero Muñoz López, Francisco José, 1964- |
| author_role |
author |
| author2 |
Guivernau Almazán, Biuse, 1988- Bonet Martínez, Jaume, 1982- Puig, Marta Perálvarez Marín, Alex Palomer, Ernest Fernàndez Busquets, Xavier Altafaj, Xavier Tajes Orduña, Marta Puig-Pijoan, Albert Vicente García, Rubén, 1978- Oliva Miguel, Baldomero Muñoz López, Francisco José, 1964- |
| author2_role |
author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Alzheimer’s disease Amyloid Immunoglobulin Fab Oligomers |
| topic |
Alzheimer’s disease Amyloid Immunoglobulin Fab Oligomers |
| description |
The amyloid beta-peptide (Aβ) plays a leading role in Alzheimer's disease (AD) physiopathology. Even though monomeric forms of Aβ are harmless to cells, Aβ can aggregate into β-sheet oligomers and fibrils, which are both neurotoxic. Therefore, one of the main therapeutic approaches to cure or delay AD onset and progression is targeting Aβ aggregation. In the present study, we show that a pool of human gamma immunoglobulins (IgG) protected cortical neurons from the challenge with Aβ oligomers, as assayed by MTT reduction, caspase-3 activation and cytoskeleton integrity. In addition, we report the inhibitory effect of IgG on Aβ aggregation, as shown by Thioflavin T assay, size exclusion chromatography and atomic force microscopy. Similar results were obtained with Palivizumab, a human anti-sincitial virus antibody. In order to dissect the important domains, we cleaved the pool of human IgG with papain to obtain Fab and Fc fragments. Using these cleaved fragments, we functionally identified Fab as the immunoglobulin fragment inhibiting Aβ aggregation, a result that was further confirmed by an in silico structural model. Interestingly, bioinformatic tools show a highly conserved structure able to bind amyloid in the Fab region. Overall, our data strongly support the inhibitory effect of human IgG on Aβ aggregation and its neuroprotective role. |
| publishDate |
2017 |
| dc.date.none.fl_str_mv |
2017 2018 2018 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10230/33732 http://dx.doi.org/10.18632/oncotarget.17074 |
| url |
http://hdl.handle.net/10230/33732 http://dx.doi.org/10.18632/oncotarget.17074 |
| dc.language.none.fl_str_mv |
Inglés |
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Inglés |
| dc.relation.none.fl_str_mv |
Oncotarget. 2017 Jun 20;8(25):41154-65 info:eu-repo/grantAgreement/ES/1PE/SAF2014-52228-R info:eu-repo/grantAgreement/ES/1PE/BIO2014-57518-R |
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http://creativecommons.org/licenses/by/3.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by/3.0/ |
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openAccess |
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application/pdf application/pdf |
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Impact Journals |
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Impact Journals |
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