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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 principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8686076/
https://www.ncbi.nlm.nih.gov/pubmed/34922273
http://dx.doi.org/10.1016/j.redox.2021.102210
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author 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_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_sort Luengo, Enrique
collection PubMed
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-Tau(P301L) 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.
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spelling pubmed-86860762021-12-30 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. Redox Biol Research Paper 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-Tau(P301L) 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. Elsevier 2021-12-10 /pmc/articles/PMC8686076/ /pubmed/34922273 http://dx.doi.org/10.1016/j.redox.2021.102210 Text en © 2021 The Authors. Published by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
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
title 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_short Implication of type 4 NADPH oxidase (NOX4) in tauopathy
title_sort implication of type 4 nadph oxidase (nox4) in tauopathy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8686076/
https://www.ncbi.nlm.nih.gov/pubmed/34922273
http://dx.doi.org/10.1016/j.redox.2021.102210
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