NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology

Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss...

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Autores: Rojo Sanchís, Ana Isabel, Pajares, Marta, Rada, Patricia, Núñez Molina, Ángel, Nevado-Holgado, Alejo J., Killik, Richard, Van Leuven, Fred, Ribe, Elena, Lovestone, Simon, Yamamoto, Masayuki, Cuadrado Pastor, Antonio
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/680568
Acceso en línea:http://hdl.handle.net/10486/680568
https://dx.doi.org/10.1016/j.redox.2017.07.006
Access Level:acceso abierto
Palabra clave:Alzheimer's disease
Neuroinflammation
NRF2
Oxidative stress
Proteotoxicity
Transcriptomics
Medicina
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spelling NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathologyRojo Sanchís, Ana IsabelPajares, MartaRada, PatriciaNúñez Molina, ÁngelNevado-Holgado, Alejo J.Killik, RichardVan Leuven, FredRibe, ElenaLovestone, SimonYamamoto, MasayukiCuadrado Pastor, AntonioAlzheimer's diseaseNeuroinflammationNRF2Oxidative stressProteotoxicityTranscriptomicsMedicinaFailure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aβ*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.This work was funded by SAF2016-76520-R of the Spanish Ministry of Economy and Competitiveness, a Pathfinder grant of the Centres of Excellence in Neurodegeneration (COEN) of the EU-Joint Program for Neurodegenerative diseases and European Regional Development Fund, Competitiveness Operational Program 2014–2020, through the grant P_37_732/2016 REDBRAINElsevier B. V.Departamento de BioquímicaFacultad de MedicinaInstituto de Investigación Sanitaria del Hospital Universitario de La Paz (IdiPAZ)Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)20172017-10-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/680568https://dx.doi.org/10.1016/j.redox.2017.07.006reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6805682026-06-23T12:46:27Z
dc.title.none.fl_str_mv NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology
title NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology
spellingShingle NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology
Rojo Sanchís, Ana Isabel
Alzheimer's disease
Neuroinflammation
NRF2
Oxidative stress
Proteotoxicity
Transcriptomics
Medicina
title_short NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology
title_full NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology
title_fullStr NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology
title_full_unstemmed NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology
title_sort NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology
dc.creator.none.fl_str_mv Rojo Sanchís, Ana Isabel
Pajares, Marta
Rada, Patricia
Núñez Molina, Ángel
Nevado-Holgado, Alejo J.
Killik, Richard
Van Leuven, Fred
Ribe, Elena
Lovestone, Simon
Yamamoto, Masayuki
Cuadrado Pastor, Antonio
author Rojo Sanchís, Ana Isabel
author_facet Rojo Sanchís, Ana Isabel
Pajares, Marta
Rada, Patricia
Núñez Molina, Ángel
Nevado-Holgado, Alejo J.
Killik, Richard
Van Leuven, Fred
Ribe, Elena
Lovestone, Simon
Yamamoto, Masayuki
Cuadrado Pastor, Antonio
author_role author
author2 Pajares, Marta
Rada, Patricia
Núñez Molina, Ángel
Nevado-Holgado, Alejo J.
Killik, Richard
Van Leuven, Fred
Ribe, Elena
Lovestone, Simon
Yamamoto, Masayuki
Cuadrado Pastor, Antonio
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Bioquímica
Facultad de Medicina
Instituto de Investigación Sanitaria del Hospital Universitario de La Paz (IdiPAZ)
Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)
dc.subject.none.fl_str_mv Alzheimer's disease
Neuroinflammation
NRF2
Oxidative stress
Proteotoxicity
Transcriptomics
Medicina
topic Alzheimer's disease
Neuroinflammation
NRF2
Oxidative stress
Proteotoxicity
Transcriptomics
Medicina
description Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aβ*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.
publishDate 2017
dc.date.none.fl_str_mv 2017
2017-10-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/680568
https://dx.doi.org/10.1016/j.redox.2017.07.006
url http://hdl.handle.net/10486/680568
https://dx.doi.org/10.1016/j.redox.2017.07.006
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier B. V.
publisher.none.fl_str_mv Elsevier B. V.
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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