Implication of type 4 NADPH oxidase (NOX4) in tauopathy

• DOI: 10.1016/j.redox.2021.102210
• Publication Date: 2021-12-10T17:16:13Z
• Authors: Enrique Luengo; Paula Trigo-Alonso; Cristina Fernánde...; Ángel Nuñez; Marta del Campo; César Porrero; Nuria García-Magro; Pilar Negredo; Sergio Senar; Cristina Sánchez-...; Juan A. Bernal; Alberto Rábano; Jeroen Hoozemans; Ana I. Casas; Harald H.H.W. Sch...; Manuela G. López
• Keywords: Tauopathy; Frontotemporal lobar degeneration; NOX4

Aggregates of the microtubule-associated protein tau are a common marker neurodegenerative diseases collectively termed as tauopathies, such Alzheimer's disease (AD) and frontotemporal dementia. Therapeutic strategies based on have failed in late stage clinical trials, suggesting that tauopathy may be consequence upstream causal mechanisms. As increasing levels reactive oxygen species (ROS) trigger aggregation or modulate degradation and, we had previously shown ROS producing enzyme NADPH oxidase 4 (NOX4) is major contributor to cellular autotoxicity, this study was designed evaluate if NOX4 implicated tauopathy. Our results show upregulated patients with lobar degeneration AD humanized mouse model induced by AVV-TauP301L brain delivery. Both, global knockout neuronal knockdown Nox4 gene mice, diminished accumulation pathological positively modified established mechanism implicates modulation autophagy-lysosomal pathway (ALP) consequently, improving macroautophagy flux. Moreover, neuronal-targeted sufficient reduce neurotoxicity prevent cognitive decline, even after induction tauopathy, direct role for Thus, unrecognized causative, mechanism-based target tauopathies blood-brain barrier permeable specific inhibitors could therapeutic potential disease.