Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy

Tauopathies are a group of neurodegenerative disorders where TAU protein is presented as aggregates or is abnormally phosphorylated, leading to alterations of axonal transport, neuronal death and neuroinflammation. Currently, there is no treatment to slow progression of these diseases. Here, we have...

Descripción completa

Detalles Bibliográficos
Autores: Cuadrado Pastor, Antonio, Kügler, Sebastian, Lastres Becker, Isabel
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:10486/710332
Acceso en línea:http://hdl.handle.net/10486/710332
https://dx.doi.org/10.1016/j.redox.2017.10.010
Access Level:acceso abierto
Palabra clave:DMF
inflammation
neurodegeneration
NRF2
oxidative stress
TAU/ GSK-3
Medicina
id ES_e7fd2e6a984b751c7a4775fd64ac375a
oai_identifier_str oai:repositorio.uam.es:10486/710332
network_acronym_str ES
network_name_str España
repository_id_str
spelling Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathyCuadrado Pastor, AntonioKügler, SebastianLastres Becker, IsabelDMFinflammationneurodegenerationNRF2oxidative stressTAU/ GSK-3MedicinaTauopathies are a group of neurodegenerative disorders where TAU protein is presented as aggregates or is abnormally phosphorylated, leading to alterations of axonal transport, neuronal death and neuroinflammation. Currently, there is no treatment to slow progression of these diseases. Here, we have investigated whether dimethyl fumarate (DMF), an inducer of the transcription factor NRF2, could mitigate tauopathy in a mouse model. The signaling pathways modulated by DMF were also studied in mouse embryonic fibroblast (MEFs) from wild type or KEAP1-deficient mice. The effect of DMF on neurodegeneration, astrocyte and microglial activation was examined in Nrf2+/+ and Nrf2−/− mice stereotaxically injected in the right hippocampus with an adeno-associated vector expressing human TAUP301L and treated daily with DMF (100 mg/kg, i.g) during three weeks. DMF induces the NRF2 transcriptional through a mechanism that involves KEAP1 but also PI3K/AKT/GSK-3-dependent pathways. DMF modulates GSK-3β activity in mouse hippocampi. Furthermore, DMF modulates TAU phosphorylation, neuronal impairment measured by calbindin-D28K and BDNF expression, and inflammatory processes involved in astrogliosis, microgliosis and pro-inflammatory cytokines production. This study reveals neuroprotective effects of DMF beyond disruption of the KEAP1/NRF2 axis by inhibiting GSK3 in a mouse model of tauopathy. Our results support repurposing of this drug for treatment of these diseasesThis work was supported by a Spanish Ministerio de Ciencia e Innovación Grant SAF2016-76520-RElsevierDepartamento de BioquímicaFacultad de Medicina20172017-11-06research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/710332https://dx.doi.org/10.1016/j.redox.2017.10.010reponame: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:10486/7103322026-06-23T12:46:27Z
dc.title.none.fl_str_mv Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy
title Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy
spellingShingle Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy
Cuadrado Pastor, Antonio
DMF
inflammation
neurodegeneration
NRF2
oxidative stress
TAU/ GSK-3
Medicina
title_short Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy
title_full Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy
title_fullStr Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy
title_full_unstemmed Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy
title_sort Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy
dc.creator.none.fl_str_mv Cuadrado Pastor, Antonio
Kügler, Sebastian
Lastres Becker, Isabel
author Cuadrado Pastor, Antonio
author_facet Cuadrado Pastor, Antonio
Kügler, Sebastian
Lastres Becker, Isabel
author_role author
author2 Kügler, Sebastian
Lastres Becker, Isabel
author2_role author
author
dc.contributor.none.fl_str_mv Departamento de Bioquímica
Facultad de Medicina
dc.subject.none.fl_str_mv DMF
inflammation
neurodegeneration
NRF2
oxidative stress
TAU/ GSK-3
Medicina
topic DMF
inflammation
neurodegeneration
NRF2
oxidative stress
TAU/ GSK-3
Medicina
description Tauopathies are a group of neurodegenerative disorders where TAU protein is presented as aggregates or is abnormally phosphorylated, leading to alterations of axonal transport, neuronal death and neuroinflammation. Currently, there is no treatment to slow progression of these diseases. Here, we have investigated whether dimethyl fumarate (DMF), an inducer of the transcription factor NRF2, could mitigate tauopathy in a mouse model. The signaling pathways modulated by DMF were also studied in mouse embryonic fibroblast (MEFs) from wild type or KEAP1-deficient mice. The effect of DMF on neurodegeneration, astrocyte and microglial activation was examined in Nrf2+/+ and Nrf2−/− mice stereotaxically injected in the right hippocampus with an adeno-associated vector expressing human TAUP301L and treated daily with DMF (100 mg/kg, i.g) during three weeks. DMF induces the NRF2 transcriptional through a mechanism that involves KEAP1 but also PI3K/AKT/GSK-3-dependent pathways. DMF modulates GSK-3β activity in mouse hippocampi. Furthermore, DMF modulates TAU phosphorylation, neuronal impairment measured by calbindin-D28K and BDNF expression, and inflammatory processes involved in astrogliosis, microgliosis and pro-inflammatory cytokines production. This study reveals neuroprotective effects of DMF beyond disruption of the KEAP1/NRF2 axis by inhibiting GSK3 in a mouse model of tauopathy. Our results support repurposing of this drug for treatment of these diseases
publishDate 2017
dc.date.none.fl_str_mv 2017
2017-11-06
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/10486/710332
https://dx.doi.org/10.1016/j.redox.2017.10.010
url http://hdl.handle.net/10486/710332
https://dx.doi.org/10.1016/j.redox.2017.10.010
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
publisher.none.fl_str_mv Elsevier
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
_version_ 1869422902762274816
score 15,300719

Similares en LA Referencia