Aging increases hippocampal DUSP2 by a membrane cholesterol loss-mediated RTK/p38MAPK activation mechanism

Numerous studies suggest that the increased activity of p38MAPK plays an important role in the abnormal immune and inflammatory response observed in the course of neurodegenerative diseases such as Alzheimer's disease. On the other hand, High levels of p38MAPK are present in the brain during no...

Descripción completa

Detalles Bibliográficos
Autores: Martín-Segura, Adrián, Casadomé-Perales, Álvaro, Fazzari, Pietro, Mas, José Manuel, Artigas, Laura, Valls, Raquel, Nebreda, Ángel R., Dotti, Carlos G.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/213579
Acceso en línea:http://hdl.handle.net/10261/213579
Access Level:acceso abierto
Palabra clave:Cholesterol
RTKs
p38MAPK
Aging
DUSP2
id ES_a723ec1a3bf14dee92efd2fd41f969cd
oai_identifier_str oai:digital.csic.es:10261/213579
network_acronym_str ES
network_name_str España
repository_id_str
spelling Aging increases hippocampal DUSP2 by a membrane cholesterol loss-mediated RTK/p38MAPK activation mechanismMartín-Segura, AdriánCasadomé-Perales, ÁlvaroFazzari, PietroMas, José ManuelArtigas, LauraValls, RaquelNebreda, Ángel R.Dotti, Carlos G.CholesterolRTKsp38MAPKAgingDUSP2Numerous studies suggest that the increased activity of p38MAPK plays an important role in the abnormal immune and inflammatory response observed in the course of neurodegenerative diseases such as Alzheimer's disease. On the other hand, High levels of p38MAPK are present in the brain during normal aging, suggesting the existence of mechanisms that keep the p38MAPK-regulated pro-inflammatory activity within physiological limits. In this study, we show that high p38MAPK activity in the hippocampus of old mice is in part due to the reduction in membrane cholesterol that constitutively occurs in the aging brain. Mechanistically, membrane cholesterol reduction increases p38MAPK activity through the stimulation of a subset of tyrosine kinase receptors (RTKs). In turn, activated p38MAPK increases the expression and activity of the phosphatase DUSP2, which is known to reduce the activity of different MAPKs, including p38MAPK. These results suggest that the loss of membrane cholesterol that constitutively occurs with age takes part in a negative-feedback loop that keeps p38MAPK activity levels within physiological range. Thus, conditions that increase p38MAPK activity such as cellular stressors or that inhibit DUSP2 will amplify inflammatory activity with its consequent deleterious functional changes.Ministry of Economy and Competitiveness grants Consolider CSD2010-00064 and SAF2013-45392 and SAF201676722 to CD. AN was supported by the Consolider grant CSD2010-0045. PF is the recipient of a Ramon y Cajal Award RYC-2014-16410 from the Spanish Ministry of Economy and Competitiveness.Ministerio de Economía y Competitividad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020192020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/213579reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/RYC-2014-16410info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-76722-Rhttp://dx.doi.org/10.3389/fneur.2019.00675Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2135792026-05-22T06:33:51Z
dc.title.none.fl_str_mv Aging increases hippocampal DUSP2 by a membrane cholesterol loss-mediated RTK/p38MAPK activation mechanism
title Aging increases hippocampal DUSP2 by a membrane cholesterol loss-mediated RTK/p38MAPK activation mechanism
spellingShingle Aging increases hippocampal DUSP2 by a membrane cholesterol loss-mediated RTK/p38MAPK activation mechanism
Martín-Segura, Adrián
Cholesterol
RTKs
p38MAPK
Aging
DUSP2
title_short Aging increases hippocampal DUSP2 by a membrane cholesterol loss-mediated RTK/p38MAPK activation mechanism
title_full Aging increases hippocampal DUSP2 by a membrane cholesterol loss-mediated RTK/p38MAPK activation mechanism
title_fullStr Aging increases hippocampal DUSP2 by a membrane cholesterol loss-mediated RTK/p38MAPK activation mechanism
title_full_unstemmed Aging increases hippocampal DUSP2 by a membrane cholesterol loss-mediated RTK/p38MAPK activation mechanism
title_sort Aging increases hippocampal DUSP2 by a membrane cholesterol loss-mediated RTK/p38MAPK activation mechanism
dc.creator.none.fl_str_mv Martín-Segura, Adrián
Casadomé-Perales, Álvaro
Fazzari, Pietro
Mas, José Manuel
Artigas, Laura
Valls, Raquel
Nebreda, Ángel R.
Dotti, Carlos G.
author Martín-Segura, Adrián
author_facet Martín-Segura, Adrián
Casadomé-Perales, Álvaro
Fazzari, Pietro
Mas, José Manuel
Artigas, Laura
Valls, Raquel
Nebreda, Ángel R.
Dotti, Carlos G.
author_role author
author2 Casadomé-Perales, Álvaro
Fazzari, Pietro
Mas, José Manuel
Artigas, Laura
Valls, Raquel
Nebreda, Ángel R.
Dotti, Carlos G.
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cholesterol
RTKs
p38MAPK
Aging
DUSP2
topic Cholesterol
RTKs
p38MAPK
Aging
DUSP2
description Numerous studies suggest that the increased activity of p38MAPK plays an important role in the abnormal immune and inflammatory response observed in the course of neurodegenerative diseases such as Alzheimer's disease. On the other hand, High levels of p38MAPK are present in the brain during normal aging, suggesting the existence of mechanisms that keep the p38MAPK-regulated pro-inflammatory activity within physiological limits. In this study, we show that high p38MAPK activity in the hippocampus of old mice is in part due to the reduction in membrane cholesterol that constitutively occurs in the aging brain. Mechanistically, membrane cholesterol reduction increases p38MAPK activity through the stimulation of a subset of tyrosine kinase receptors (RTKs). In turn, activated p38MAPK increases the expression and activity of the phosphatase DUSP2, which is known to reduce the activity of different MAPKs, including p38MAPK. These results suggest that the loss of membrane cholesterol that constitutively occurs with age takes part in a negative-feedback loop that keeps p38MAPK activity levels within physiological range. Thus, conditions that increase p38MAPK activity such as cellular stressors or that inhibit DUSP2 will amplify inflammatory activity with its consequent deleterious functional changes.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/213579
url http://hdl.handle.net/10261/213579
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/RYC-2014-16410
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-76722-R
http://dx.doi.org/10.3389/fneur.2019.00675
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
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
_version_ 1869415754340761600
score 15,812429

Similares en LA Referencia