Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.14.338954v1?rss=1 Authors: Luengo, E., Trigo-Alonso, P., Fernandez-Mendivil, C., Nunez, A., del Campo, M., Porrero, C., Garcia-Magro, N., Negredo, P., Sanchez, C., Bernal, J. A., Rabano, A., Hoozemans, J., Casas, A. I., Schmidt, H. H., Cuervo, A. M., Lopez, M. G. Abstract: Approximately 44 million people worldwide live with Alzheimer's disease (AD) or a related form of dementia. Aggregates of the microtubule-associated protein tau are a common marker of these neurodegenerative diseases collectively termed as tauopathies. However, all therapeutic attempts based on tau have failed, suggesting that tau may only indicate a higher-level causal mechanism. For example, increasing levels of reactive oxygen species (ROS) may trigger protein aggregation or modulate protein degradation. Here we show that type 4 NADPH oxidase (NOX), the most abundant isoform of the only dedicated reactive oxygen producing enzyme family, is upregulated in dementia and AD patients and in a humanized mouse model of tauopathy. 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). Moreover, neuronal-targeted NOX4 knockdown was sufficient to reduce neurotoxicity and prevented cognitive decline, suggesting a direct and causal role for neuronal NOX4. Thus, NOX4 is a previously unrecognized causal, mechanism-based target in tauopathies and blood-brain barrier permeable specific NOX4 inhibitors could have therapeutic potential even in established disease. Copy rights belong to original authors. Visit the link for more info