Neuronal NOX4 knockdown alleviates pathological tau-related alterations in a humanized mouse model of tauopathy

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.

doi:10.1101/2020.10.14.338954

bioRxiv · 10.1101/2020.10.14.338954

Neuronal NOX4 knockdown alleviates pathological tau-related alterations in a humanized mouse model of tauopathy

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.

View original source ↗Export metadata ↓

Abstract

Approximately 44 million people worldwide live with Alzheimers 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/338954v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1dac496org.highwire.dtl.DTLVardef@1a07dd5org.highwire.dtl.DTLVardef@1a5653aorg.highwire.dtl.DTLVardef@198f3e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

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.. 2020-10-14. Neuronal NOX4 knockdown alleviates pathological tau-related alterations in a humanized mouse model of tauopathy. https://doi.org/10.1101/2020.10.14.338954

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗

bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗

bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗