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Título
Implication of type 4 NADPH oxidase (NOX4) in tauopathy.
Autor(es)
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
Fecha de publicación
2022-02
Cita
Redox Biol. 2022 Feb;49:102210
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
MESH
Alzheimer Disease | Frontotemporal Dementia | Tauopathies | Animals | Brain | Humans | Mice | NADPH Oxidase 4 | NADPH Oxidases | tau Proteins
Versión en línea
DOI
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