Amyloid-β peptide nitrotyrosination stabilizes oligomers and enhances NMDAR-mediated toxicity

Guivernau Almazán, Biuse, 1988-; Bonet Martínez, Jaume, 1982-; Valls Comamala, Victòria, 1987-; Bosch Morató, Mònica, 1986-; Godoy Zeballos, Juan Alejandro, 1959-; Inestrosa, Nibaldo C.; Perálvarez Marín, Alex; Fernández-Busquets, Xavier; Andreu Martínez, David; Oliva Miguel, Baldomero; Muñoz López, Francisco José, 1964-

Amyloid-β peptide nitrotyrosination stabilizes oligomers and enhances NMDAR-mediated toxicity

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dc.contributor.author Guivernau Almazán, Biuse, 1988-ca
dc.contributor.author Bonet Martínez, Jaume, 1982-ca
dc.contributor.author Valls Comamala, Victòria, 1987-ca
dc.contributor.author Bosch Morató, Mònica, 1986-ca
dc.contributor.author Godoy Zeballos, Juan Alejandro, 1959-ca
dc.contributor.author Inestrosa, Nibaldo C.ca
dc.contributor.author Perálvarez Marín, Alexca
dc.contributor.author Fernández-Busquets, Xavierca
dc.contributor.author Andreu Martínez, Davidca
dc.contributor.author Oliva Miguel, Baldomeroca
dc.contributor.author Muñoz López, Francisco José, 1964-ca
dc.date.accessioned 2018-07-11T10:48:23Z
dc.date.available 2018-07-11T10:48:23Z
dc.date.issued 2016
dc.description.abstract Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-β peptide (Aβ). Monomeric soluble Aβ can switch from helicoidal to β-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. Aβ can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that Aβ nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an Aβ analog containing a single residue (H to E) replacement that mimics the behavior of nitrated Aβ related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated Aβ oligomers was observed. Our results show that Aβ nitrotyrosination is a post-translational modification that increases Aβ synaptotoxicity. SIGNIFICANCE STATEMENT: We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-β (Aβ) favors the stabilization of highly toxic oligomers and inhibits the formation of Aβ fibrils. The nitrated Aβ oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.
dc.description.sponsorship This work was supported by Spanish Plan Estatal de I+D+I 2013-2016 and the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Grants PI13/00408 and Red HERACLES RD12/0042/0014 and FEDER Funds, Spanish Ministerio de Economía y Competitividad BIO2014-57518-R, BIO2014-52872-R, and AGL2014-52395-C2-2-R and FEDER Funds, the Generalitat de Catalunya (Spain) 2014-SGR-938, and Chilean Funds for Science CONICYTPFB 12/2007 and FONDECYT N° 1160724. A.P.-M. was the recipient of the Universitat Autònoma de Barcelona-Programa Banco de Santander Fellowship
dc.format.mimetype application/pdf
dc.identifier.citation Guivernau B, Bonet J, Valls-Comamala V, Bosch-Morató M, Godoy JA, Inestrosa NC et al. Amyloid-β peptide nitrotyrosination stabilizes oligomers and enhances NMDAR-mediated toxicity. J Neurosci. 2016 Nov 16;36(46):11693-703. DOI: 10.1523/JNEUROSCI.1081-16.2016
dc.identifier.doi http://dx.doi.org/10.1523/JNEUROSCI.1081-16.2016
dc.identifier.issn 0270-6474
dc.identifier.uri http://hdl.handle.net/10230/35137
dc.language.iso eng
dc.publisher Society for Neuroscienceca
dc.relation.ispartof Journal of Neuroscience. 2016 Nov 16;36(46):11693-703
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2014-57518-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2014-52872-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/AGL2014-52395-C2-2-R
dc.rights © Biuse Guivernau, Jaume Bonet, Victòria Valls-Comamala et al. Published by the Society for Neuroscience https://doi.org/10.1523/JNEUROSCI.1081-16.2016. The work is published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, as described at https://creativecommons.org/licenses/by/4.0/
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.other Alzheimer, Malaltia d'
dc.subject.other Amiloide
dc.subject.other Química -- Models
dc.subject.other Neurones -- Metabolisme
dc.title Amyloid-β peptide nitrotyrosination stabilizes oligomers and enhances NMDAR-mediated toxicityca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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