Implication of type 4 NADPH oxidase (NOX4) in tauopathy

Redox Biology

Juan A. Bernal¹  César Porrero²  Ángel Nuñez²  Paula Trigo-Alonso²  Sergio Senar³  Nuria García-Magro³  Cristina Sánchez-Ramos³  Alberto Rábano³  Pilar Negredo⁴  Manuela G. López⁵  Jeroen Hoozemans⁶  Marta del Campo⁷  Enrique Luengo⁷  Cristina Fernández-Mendívil⁷  Harald H.H.W. Schmidt⁸  Ana I. Casas⁸ 

[1]Facultad de Ciencias de la Salud, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain

[2]Instituto de Investigación Sanitario (IIS-IP), Hospital Universitario de la Princesa, Madrid, Spain

[3]Department of Anatomy, Histology and Neuroscience, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain

[4]Department of Health and Pharmaceutical Science, Faculty of Pharmacy, San Pablo CEU University, Montepríncipe, Alcorcón, Spain

[5]Department of Neuropathology and Tissue Bank, Unidad de Investigación Proyecto Alzheimer, Fundación CIEN, Instituto de Salud Carlos III, Madrid, Spain

[6]Dr. Target Machine Learning. Calle Alejo Carpentier 13, Alcala de Henares, 28806, Madrid, Spain

[7]Instituto Teófilo Hernando for Drug Discovery, Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain

[8]Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

关键词: Alzheimer's disease;    Tauopathy;    Autophagy;    NADPH oxidases;    NOX4;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown