Implication of type 4 NADPH oxidase (NOX4) in tauopathy.

Luengo, Enrique; Trigo-Alonso, Paula; Fernández-Mendívil, Cristina; Nuñez, Ángel; Campo, Marta Del; Porrero, César; García-Magro, Nuria; Negredo, Pilar; Senar, Sergio; Sánchez-Ramos, Cristina; Bernal, Juan A; Rábano, Alberto; Hoozemans, Jeroen; Casas, Ana I; Schmidt, Harald H H W; López, Manuela G

Implication of type 4 NADPH oxidase (NOX4) in tauopathy.

Aggregates of the microtubule-associated protein tau are a common marker of neurodegenerative diseases collectively termed as tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia. Therapeutic strategies based on tau have failed in late stage clinical trials, suggesting that...

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Autores:	Luengo, Enrique, Trigo-Alonso, Paula, Fernández-Mendívil, Cristina, Nuñez, Ángel, Campo, Marta Del, Porrero, César, García-Magro, Nuria, Negredo, Pilar, Senar, Sergio, Sánchez-Ramos, Cristina, Bernal, Juan A, Rábano, Alberto, Hoozemans, Jeroen, Casas, Ana I, Schmidt, Harald H H W, López, Manuela G
Tipo de recurso:	artículo
Fecha de publicación:	2022
País:	España
Institución:	Instituto de Salud Carlos III (ISCIII)
Repositorio:	Repisalud
Idioma:	inglés
OAI Identifier:	oai:repisalud.isciii.es:20.500.12105/15722
Acceso en línea:	http://hdl.handle.net/20.500.12105/15722
Access Level:	acceso abierto
Palabra clave:	Alzheimer Disease Frontotemporal Dementia Tauopathies Animals Brain Humans Mice NADPH Oxidase 4 NADPH Oxidases tau Proteins

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spelling	Implication of type 4 NADPH oxidase (NOX4) in tauopathy.Luengo, EnriqueTrigo-Alonso, PaulaFernández-Mendívil, CristinaNuñez, ÁngelCampo, Marta DelPorrero, CésarGarcía-Magro, NuriaNegredo, PilarSenar, SergioSánchez-Ramos, CristinaBernal, Juan ARábano, AlbertoHoozemans, JeroenCasas, Ana ISchmidt, Harald H H WLópez, Manuela GAlzheimer DiseaseFrontotemporal DementiaTauopathiesAnimalsBrainHumansMiceNADPH Oxidase 4NADPH Oxidasestau ProteinsAggregates of the microtubule-associated protein tau are a common marker of neurodegenerative diseases collectively termed as tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia. Therapeutic strategies based on tau have failed in late stage clinical trials, suggesting that tauopathy may be the consequence of upstream causal mechanisms. As increasing levels of reactive oxygen species (ROS) may trigger protein aggregation or modulate protein degradation and, we had previously shown that the ROS producing enzyme NADPH oxidase 4 (NOX4) is a major contributor to cellular autotoxicity, this study was designed to evaluate if NOX4 is implicated in tauopathy. Our results show that NOX4 is upregulated in patients with frontotemporal lobar degeneration and AD patients and, in a humanized mouse model of tauopathy induced by AVV-TauP301L brain delivery. Both, global knockout and neuronal knockdown of the Nox4 gene in mice, diminished the accumulation of pathological tau and positively modified established tauopathy by a mechanism that implicates modulation of the autophagy-lysosomal pathway (ALP) and, consequently, improving the macroautophagy flux. Moreover, neuronal-targeted NOX4 knockdown was sufficient to reduce neurotoxicity and prevent cognitive decline, even after induction of tauopathy, suggesting a direct and causal role for neuronal NOX4 in tauopathy. Thus, NOX4 is a previously unrecognized causative, mechanism-based target in tauopathies and blood-brain barrier permeable specific NOX4 inhibitors could have therapeutic potential even in established disease.ElsevierMinisterio de Ciencia, Innovación y Universidades (España)Comunidad de Madrid (España)Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)20232023-03-2720222022-02-0120222022-02-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/15722reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/157222026-06-12T12:43:37Z
dc.title.none.fl_str_mv	Implication of type 4 NADPH oxidase (NOX4) in tauopathy.
title	Implication of type 4 NADPH oxidase (NOX4) in tauopathy.
spellingShingle	Implication of type 4 NADPH oxidase (NOX4) in tauopathy. Luengo, Enrique Alzheimer Disease Frontotemporal Dementia Tauopathies Animals Brain Humans Mice NADPH Oxidase 4 NADPH Oxidases tau Proteins
title_short	Implication of type 4 NADPH oxidase (NOX4) in tauopathy.
title_full	Implication of type 4 NADPH oxidase (NOX4) in tauopathy.
title_fullStr	Implication of type 4 NADPH oxidase (NOX4) in tauopathy.
title_full_unstemmed	Implication of type 4 NADPH oxidase (NOX4) in tauopathy.
title_sort	Implication of type 4 NADPH oxidase (NOX4) in tauopathy.
dc.creator.none.fl_str_mv	Luengo, Enrique Trigo-Alonso, Paula Fernández-Mendívil, Cristina Nuñez, Ángel Campo, Marta Del Porrero, César García-Magro, Nuria Negredo, Pilar Senar, Sergio Sánchez-Ramos, Cristina Bernal, Juan A Rábano, Alberto Hoozemans, Jeroen Casas, Ana I Schmidt, Harald H H W López, Manuela G
author	Luengo, Enrique
author_facet	Luengo, Enrique Trigo-Alonso, Paula Fernández-Mendívil, Cristina Nuñez, Ángel Campo, Marta Del Porrero, César García-Magro, Nuria Negredo, Pilar Senar, Sergio Sánchez-Ramos, Cristina Bernal, Juan A Rábano, Alberto Hoozemans, Jeroen Casas, Ana I Schmidt, Harald H H W López, Manuela G
author_role	author
author2	Trigo-Alonso, Paula Fernández-Mendívil, Cristina Nuñez, Ángel Campo, Marta Del Porrero, César García-Magro, Nuria Negredo, Pilar Senar, Sergio Sánchez-Ramos, Cristina Bernal, Juan A Rábano, Alberto Hoozemans, Jeroen Casas, Ana I Schmidt, Harald H H W López, Manuela G
author2_role	author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Ministerio de Ciencia, Innovación y Universidades (España) Comunidad de Madrid (España) Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
dc.subject.none.fl_str_mv	Alzheimer Disease Frontotemporal Dementia Tauopathies Animals Brain Humans Mice NADPH Oxidase 4 NADPH Oxidases tau Proteins
topic	Alzheimer Disease Frontotemporal Dementia Tauopathies Animals Brain Humans Mice NADPH Oxidase 4 NADPH Oxidases tau Proteins
description	Aggregates of the microtubule-associated protein tau are a common marker of neurodegenerative diseases collectively termed as tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia. Therapeutic strategies based on tau have failed in late stage clinical trials, suggesting that tauopathy may be the consequence of upstream causal mechanisms. As increasing levels of reactive oxygen species (ROS) may trigger protein aggregation or modulate protein degradation and, we had previously shown that the ROS producing enzyme NADPH oxidase 4 (NOX4) is a major contributor to cellular autotoxicity, this study was designed to evaluate if NOX4 is implicated in tauopathy. Our results show that NOX4 is upregulated in patients with frontotemporal lobar degeneration and AD patients and, in a humanized mouse model of tauopathy induced by AVV-TauP301L brain delivery. Both, global knockout and neuronal knockdown of the Nox4 gene in mice, diminished the accumulation of pathological tau and positively modified established tauopathy by a mechanism that implicates modulation of the autophagy-lysosomal pathway (ALP) and, consequently, improving the macroautophagy flux. Moreover, neuronal-targeted NOX4 knockdown was sufficient to reduce neurotoxicity and prevent cognitive decline, even after induction of tauopathy, suggesting a direct and causal role for neuronal NOX4 in tauopathy. Thus, NOX4 is a previously unrecognized causative, mechanism-based target in tauopathies and blood-brain barrier permeable specific NOX4 inhibitors could have therapeutic potential even in established disease.
publishDate	2022
dc.date.none.fl_str_mv	2022 2022-02-01 2022 2022-02-01 2023 2023-03-27
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 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/20.500.12105/15722
url	http://hdl.handle.net/20.500.12105/15722
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 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/
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 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/
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:Repisalud instname:Instituto de Salud Carlos III (ISCIII)
instname_str	Instituto de Salud Carlos III (ISCIII)
reponame_str	Repisalud
collection	Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,811543

Implication of type 4 NADPH oxidase (NOX4) in tauopathy.

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