Neuronal NOX4 knockdown alleviates pathological tau-related alterations in a humanized mouse model of tauopathy
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 theNox4gene 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 <jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="338954v1_ufig1" position="float" orientation="portrait" /></jats:fig>.
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 23. Nov. Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Luengo, Enrique [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
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| doi: |
10.1101/2020.10.14.338954 |
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| PPN (Katalog-ID): |
XBI019129033 |
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| 100 | 1 | |a Luengo, Enrique |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Neuronal NOX4 knockdown alleviates pathological tau-related alterations in a humanized mouse model of tauopathy |
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| 520 | |a 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 theNox4gene 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 <jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="338954v1_ufig1" position="float" orientation="portrait" /></jats:fig> | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Trigo-Alonso, Paula |e verfasserin |4 aut | |
| 700 | 1 | |a Fernández-Mendívil, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Nuñez, Ángel |e verfasserin |4 aut | |
| 700 | 1 | |a del Campo, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Porrero, César |e verfasserin |4 aut | |
| 700 | 1 | |a García-Magro, Nuria |e verfasserin |4 aut | |
| 700 | 1 | |a Negredo, Pilar |e verfasserin |4 aut | |
| 700 | 1 | |a Sánchez-Ramos, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Bernal, Juan A. |e verfasserin |4 aut | |
| 700 | 1 | |a Rábano, Alberto |e verfasserin |4 aut | |
| 700 | 1 | |a Hoozemans, Jeroen |e verfasserin |4 aut | |
| 700 | 1 | |a Casas, Ana I |e verfasserin |4 aut | |
| 700 | 1 | |a Schmidt, Harald H.H.W |e verfasserin |4 aut | |
| 700 | 1 | |a Cuervo, Ana María |e verfasserin |4 aut | |
| 700 | 1 | |a López, Manuela G. |e verfasserin |4 aut | |
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