The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers

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• dc.contributor.author Valls Comamala, Victòria, 1987-ca
• dc.contributor.author Guivernau Almazán, Biuse, 1988-ca
• dc.contributor.author Bonet Martínez, Jaume, 1982-ca
• dc.contributor.author Puig, Martaca
• dc.contributor.author Perálvarez Marín, Alexca
• dc.contributor.author Palomer, Ernestca
• dc.contributor.author Fernàndez Busquets, Xavierca
• dc.contributor.author Altafaj, Xavierca
• dc.contributor.author Tajes Orduña, Martaca
• dc.contributor.author Puig Pijoan, Albertca
• dc.contributor.author Vicente García, Rubén, 1978-ca
• dc.contributor.author Oliva Miguel, Baldomeroca
• dc.contributor.author Muñoz López, Francisco José, 1964-ca
• dc.date.accessioned 2018-01-23T13:08:34Z
• dc.date.available 2018-01-23T13:08:34Z
• dc.date.issued 2017
• dc.description.abstract 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.
• dc.description.sponsorship 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)
• dc.format.mimetype application/pdfca
• dc.identifier.citation Valls-Comamala V, Guivernau B, Bonet J, Puig M, Perálvarez-Marín A et al. The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers. Oncotarget. 2017 Jun 20;8(25):41154-65. DOI: 10.18632/oncotarget.17074
• dc.identifier.doi http://dx.doi.org/10.18632/oncotarget.17074
• dc.identifier.issn 1949-2553
• dc.identifier.uri http://hdl.handle.net/10230/33732
• dc.language.iso eng
• dc.publisher Impact Journalsca
• dc.relation.ispartof Oncotarget. 2017 Jun 20;8(25):41154-65
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-52228-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2014-57518-R
• dc.rights Valls-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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/3.0/
• dc.subject.keyword Alzheimer’s disease
• dc.subject.keyword Amyloid
• dc.subject.keyword Immunoglobulin
• dc.subject.keyword Fab
• dc.subject.keyword Oligomers
• dc.title The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomersca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion