NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model

López-Sampere, Yaiza; Mengod, Pol; Roca-Pereira, Sergio; Vinyals, Antònia; Mato-Blanco, Xoel; Vela-Martínez, Marta; Dakterzada, Farida; Romero, Leila; Santamaría Martínez, Enrique; Fernández Irigoyen, Joaquín; Ferrer, Isidro (Ferrer Abizanda); Povedano Panades, Mónica; Río Fernández, José Antonio del; Santpere Baró, Gabriel; Portero Otin, Manuel; Piñol Ripoll, Gerard; Andrés-Benito, Pol

NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model

Background Nuclear factor erythroid 2–related factor 2 (NRF2) regulates antioxidant defenses and protects against neurodegeneration, including Alzheimer's disease (AD). Its age-related decline disrupts redox balance and increases neuronal vulnerability, but the early hippocampal effects rem...

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Autores:	López-Sampere, Yaiza, Mengod, Pol, Roca-Pereira, Sergio, Vinyals, Antònia, Mato-Blanco, Xoel, Vela-Martínez, Marta, Dakterzada, Farida, Romero, Leila, Santamaría Martínez, Enrique, Fernández Irigoyen, Joaquín, Ferrer, Isidro (Ferrer Abizanda), Povedano Panades, Mónica, Río Fernández, José Antonio del, Santpere Baró, Gabriel, Portero Otin, Manuel, Piñol Ripoll, Gerard, Andrés-Benito, Pol
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2026
País:	España
Institución:	Universidad de Barcelona
Repositorio:	Dipòsit Digital de la UB
OAI Identifier:	oai:dnet:ubarcelona__::1d1f5fa3b796dd97edee22400ebb2bf1
Acceso en línea:	https://hdl.handle.net/2445/229379
Access Level:	acceso abierto
Palabra clave:	Malaltia d&apos Alzheimer Envelliment cerebral Neurogenètica Alzheimer&apos s disease Aging brain Neurogenetics

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spelling	NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse modelLópez-Sampere, YaizaMengod, PolRoca-Pereira, SergioVinyals, AntòniaMato-Blanco, XoelVela-Martínez, MartaDakterzada, FaridaRomero, LeilaSantamaría Martínez, EnriqueFernández Irigoyen, JoaquínFerrer, Isidro (Ferrer Abizanda)Povedano Panades, MónicaRío Fernández, José Antonio delSantpere Baró, GabrielPortero Otin, ManuelPiñol Ripoll, GerardAndrés-Benito, PolMalaltia d&aposAlzheimerEnvelliment cerebralNeurogenèticaAlzheimer&aposs diseaseAging brainNeurogeneticsBackground Nuclear factor erythroid 2–related factor 2 (NRF2) regulates antioxidant defenses and protects against neurodegeneration, including Alzheimer's disease (AD). Its age-related decline disrupts redox balance and increases neuronal vulnerability, but the early hippocampal effects remain unclear. Here, we tested whether NRF2 loss affects tau seeding and spreading in a PHF-tau–inoculated mouse model, contributing to accelerated aging. Methodology Three-month-old NRF2-knockout (Nfe2l2−/−) and wild-type (WT) mice received hippocampal inoculations of human AD-derived PHF-tau, and tau propagation was analyzed after three months. To elucidate the molecular underpinnings of the observed changes, we performed integrative phosphoproteotranscriptomic analyses of hippocampal tissue, supported by RT-qPCR and Western blot validation. Results PHF-tau inoculation at 3 months of age in Nfe2l2−/− mice, surprisingly, exhibited markedly reduced tau seeding and spreading compared to WT after 3 months of incubation. Molecular characterization of the Nfe2l2−/− hippocampus was carried out to unravel the molecular changes associated with impaired tau propagation. Transcriptomic profiling revealed 745 deregulated genes in Nfe2l2−/− mice, characterized by upregulation of immune and metabolic pathways but downregulation of oxidative stress and redox-related genes. RT-qPCR confirmed diminished expression of antioxidant enzymes and anti-inflammatory receptors, alongside altered astrocytic markers. Proteomic analysis identified 157 dysregulated proteins associated with mitochondrial, synaptic, and inflammatory processes, while phosphoproteomics detected 824 altered phosphosites enriched in cytoskeletal and synaptic networks. Western blot showed increased GFAP-C-term, AQP4, 8-OHdG, and MDAL, with reduced GSTM2 expression. Notably, total and 4R-tau levels were decreased, while 3R-tau was elevated in Nfe2l2−/− mice. Conclusion Our findings suggest that NRF2 loss induces a hippocampal state marked by impaired antioxidant defenses, astrocytic remodeling, and disrupted tau isoform balance. This environment, while metabolically altered, paradoxically hinders tau propagation, highlighting NRF2 as a key regulator of both redox and cellular maturity programs essential for tau spread and as a potential therapeutic target in tauopathies.Elsevier B.V.2026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/229379Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.redox.2026.104068Redox Biology, 2026, vol. 91, p. 104068https://doi.org/10.1016/j.redox.2026.104068cc-by-nc (c) López-Sampere, Yaiza et al., 2026http://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:dnet:ubarcelona__::1d1f5fa3b796dd97edee22400ebb2bf12026-05-27T06:46:51Z
dc.title.none.fl_str_mv	NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model
title	NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model
spellingShingle	NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model López-Sampere, Yaiza Malaltia d&apos Alzheimer Envelliment cerebral Neurogenètica Alzheimer&apos s disease Aging brain Neurogenetics
title_short	NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model
title_full	NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model
title_fullStr	NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model
title_full_unstemmed	NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model
title_sort	NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model
dc.creator.none.fl_str_mv	López-Sampere, Yaiza Mengod, Pol Roca-Pereira, Sergio Vinyals, Antònia Mato-Blanco, Xoel Vela-Martínez, Marta Dakterzada, Farida Romero, Leila Santamaría Martínez, Enrique Fernández Irigoyen, Joaquín Ferrer, Isidro (Ferrer Abizanda) Povedano Panades, Mónica Río Fernández, José Antonio del Santpere Baró, Gabriel Portero Otin, Manuel Piñol Ripoll, Gerard Andrés-Benito, Pol
author	López-Sampere, Yaiza
author_facet	López-Sampere, Yaiza Mengod, Pol Roca-Pereira, Sergio Vinyals, Antònia Mato-Blanco, Xoel Vela-Martínez, Marta Dakterzada, Farida Romero, Leila Santamaría Martínez, Enrique Fernández Irigoyen, Joaquín Ferrer, Isidro (Ferrer Abizanda) Povedano Panades, Mónica Río Fernández, José Antonio del Santpere Baró, Gabriel Portero Otin, Manuel Piñol Ripoll, Gerard Andrés-Benito, Pol
author_role	author
author2	Mengod, Pol Roca-Pereira, Sergio Vinyals, Antònia Mato-Blanco, Xoel Vela-Martínez, Marta Dakterzada, Farida Romero, Leila Santamaría Martínez, Enrique Fernández Irigoyen, Joaquín Ferrer, Isidro (Ferrer Abizanda) Povedano Panades, Mónica Río Fernández, José Antonio del Santpere Baró, Gabriel Portero Otin, Manuel Piñol Ripoll, Gerard Andrés-Benito, Pol
author2_role	author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Malaltia d&apos Alzheimer Envelliment cerebral Neurogenètica Alzheimer&apos s disease Aging brain Neurogenetics
topic	Malaltia d&apos Alzheimer Envelliment cerebral Neurogenètica Alzheimer&apos s disease Aging brain Neurogenetics
description	Background Nuclear factor erythroid 2–related factor 2 (NRF2) regulates antioxidant defenses and protects against neurodegeneration, including Alzheimer's disease (AD). Its age-related decline disrupts redox balance and increases neuronal vulnerability, but the early hippocampal effects remain unclear. Here, we tested whether NRF2 loss affects tau seeding and spreading in a PHF-tau–inoculated mouse model, contributing to accelerated aging. Methodology Three-month-old NRF2-knockout (Nfe2l2−/−) and wild-type (WT) mice received hippocampal inoculations of human AD-derived PHF-tau, and tau propagation was analyzed after three months. To elucidate the molecular underpinnings of the observed changes, we performed integrative phosphoproteotranscriptomic analyses of hippocampal tissue, supported by RT-qPCR and Western blot validation. Results PHF-tau inoculation at 3 months of age in Nfe2l2−/− mice, surprisingly, exhibited markedly reduced tau seeding and spreading compared to WT after 3 months of incubation. Molecular characterization of the Nfe2l2−/− hippocampus was carried out to unravel the molecular changes associated with impaired tau propagation. Transcriptomic profiling revealed 745 deregulated genes in Nfe2l2−/− mice, characterized by upregulation of immune and metabolic pathways but downregulation of oxidative stress and redox-related genes. RT-qPCR confirmed diminished expression of antioxidant enzymes and anti-inflammatory receptors, alongside altered astrocytic markers. Proteomic analysis identified 157 dysregulated proteins associated with mitochondrial, synaptic, and inflammatory processes, while phosphoproteomics detected 824 altered phosphosites enriched in cytoskeletal and synaptic networks. Western blot showed increased GFAP-C-term, AQP4, 8-OHdG, and MDAL, with reduced GSTM2 expression. Notably, total and 4R-tau levels were decreased, while 3R-tau was elevated in Nfe2l2−/− mice. Conclusion Our findings suggest that NRF2 loss induces a hippocampal state marked by impaired antioxidant defenses, astrocytic remodeling, and disrupted tau isoform balance. This environment, while metabolically altered, paradoxically hinders tau propagation, highlighting NRF2 as a key regulator of both redox and cellular maturity programs essential for tau spread and as a potential therapeutic target in tauopathies.
publishDate	2026
dc.date.none.fl_str_mv	2026
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/2445/229379
url	https://hdl.handle.net/2445/229379
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Reproducció del document publicat a: https://doi.org/10.1016/j.redox.2026.104068 Redox Biology, 2026, vol. 91, p. 104068 https://doi.org/10.1016/j.redox.2026.104068
dc.rights.none.fl_str_mv	cc-by-nc (c) López-Sampere, Yaiza et al., 2026 http://creativecommons.org/licenses/by-nc/4.0/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	cc-by-nc (c) López-Sampere, Yaiza et al., 2026 http://creativecommons.org/licenses/by-nc/4.0/
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	Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona
instname_str	Universidad de Barcelona
reponame_str	Dipòsit Digital de la UB
collection	Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,198674

NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model

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