Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease

Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Aβ42 versus Aβ40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects...

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Detalles Bibliográficos
Autores: Guix, Francesc X., Dotti, Carlos G., Strooper, Bart de
Tipo de recurso: artículo
Fecha de publicación:2012
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/113969
Acceso en línea:http://hdl.handle.net/10261/113969
Access Level:acceso abierto
Palabra clave:Ageing
Gamma-secretase
Peroxynitrite
Presenilin-1
Alzheimer’s disease
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spelling Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's diseaseGuix, Francesc X.Dotti, Carlos G.Strooper, Bart deAgeingGamma-secretasePeroxynitritePresenilin-1Alzheimer’s diseaseInherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Aβ42 versus Aβ40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects amyloid beta-peptide (Aβ) generation as well. Here we demonstrate that the secretion of Aβ is enhanced in an in vitro model of neuronal ageing, correlating with an increase in γ-secretase complex formation. Moreover we found that peroxynitrite (ONOO -), produced by the reaction of superoxide anion with nitric oxide, promoted the nitrotyrosination of presenilin 1 (PS1), the catalytic subunit of γ-secretase. This was associated with an increased association of the two PS1 fragments, PS1-CTF and PS1-NTF, which constitute the active catalytic centre. Furthermore, we found that peroxynitrite shifted the production of Aβ towards Aβ 42 and increased the Aβ 42/Aβ 40 ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD. © 2012 EMBO Molecular Medicine.Fund for Scientific Research, Flanders; the K.U.Leuven; the VIB, Methusalem (K.U.Leuven and the Flemisch government); the Foundation for Alzheimer Research (SAO/FRMA); European Research council; NIH AG15379 (OB); Spanish Ministry of Science and Innovation SAF 2010-14906; Consolider 2010-00045 (CGD); Spanish Ministery of Health (Fondo de Investigación Sanitaria-PI10/00587 and Red HERACLES RD06/0009); The European FEDER Fundings; and Fundació La Marató de TV3 (Catalonia; Spain; no. 100310)Peer ReviewedWiley-VCHResearch Foundation - FlandersUniversity of LeuvenMinistry of the Flemish Community (Belgium)Foundation for Alzheimer ResearchEuropean CommissionNational Institutes of Health (US)Ministerio de Ciencia e Innovación (España)Ministerio de Sanidad y Consumo (España)Federación Española de Enfermedades RarasFundació La Marató de TV32015201520122015info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/113969reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglésinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1139692026-05-22T06:33:51Z
dc.title.none.fl_str_mv Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
title Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
spellingShingle Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
Guix, Francesc X.
Ageing
Gamma-secretase
Peroxynitrite
Presenilin-1
Alzheimer’s disease
title_short Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
title_full Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
title_fullStr Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
title_full_unstemmed Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
title_sort Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease
dc.creator.none.fl_str_mv Guix, Francesc X.
Dotti, Carlos G.
Strooper, Bart de
author Guix, Francesc X.
author_facet Guix, Francesc X.
Dotti, Carlos G.
Strooper, Bart de
author_role author
author2 Dotti, Carlos G.
Strooper, Bart de
author2_role author
author
dc.contributor.none.fl_str_mv Research Foundation - Flanders
University of Leuven
Ministry of the Flemish Community (Belgium)
Foundation for Alzheimer Research
European Commission
National Institutes of Health (US)
Ministerio de Ciencia e Innovación (España)
Ministerio de Sanidad y Consumo (España)
Federación Española de Enfermedades Raras
Fundació La Marató de TV3
dc.subject.none.fl_str_mv Ageing
Gamma-secretase
Peroxynitrite
Presenilin-1
Alzheimer’s disease
topic Ageing
Gamma-secretase
Peroxynitrite
Presenilin-1
Alzheimer’s disease
description Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Aβ42 versus Aβ40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects amyloid beta-peptide (Aβ) generation as well. Here we demonstrate that the secretion of Aβ is enhanced in an in vitro model of neuronal ageing, correlating with an increase in γ-secretase complex formation. Moreover we found that peroxynitrite (ONOO -), produced by the reaction of superoxide anion with nitric oxide, promoted the nitrotyrosination of presenilin 1 (PS1), the catalytic subunit of γ-secretase. This was associated with an increased association of the two PS1 fragments, PS1-CTF and PS1-NTF, which constitute the active catalytic centre. Furthermore, we found that peroxynitrite shifted the production of Aβ towards Aβ 42 and increased the Aβ 42/Aβ 40 ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD. © 2012 EMBO Molecular Medicine.
publishDate 2012
dc.date.none.fl_str_mv 2012
2015
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/113969
url http://hdl.handle.net/10261/113969
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Wiley-VCH
publisher.none.fl_str_mv Wiley-VCH
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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