p47phox deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD
Open accessAbstract
Background: Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive impairment. The aggregation of amyloid β (Aβ) and hyperphosphorylated tau protein are two major pathological features of AD. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) has been indicated in Aβ pathology; however, whether and how it affects tau pathology are not yet clear. Methods: The role of NOX2 in cognitive function, amyloid plaque formation, and tau hyperphosphorylation were examined in APP/PS1 transgenic mice mated with p47 phox -deficient mice (with deletion of the gene of neutrophil cytosolic factor 1, Ncf1 ) and/or in p47 phox -deficient mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ). The cognitive and non-cognitive functions in these mice were assessed by Morris water maze, Rotarod test, open field, and elevated plus maze. Aβ levels, amyloid plaques, p47 phox expression, and astrocyte activation were evaluated using immunofluorescence staining, ELISA, and/or Western blotting. Cultured primary neuronal cells were treated with okadaic acid or conditioned media (CM) from high glucose-stimulated primary astrocytes. The alteration in tau pathology was determined using Western blotting and immunofluorescence staining. Results: Deletion of the gene coding for p47 phox , the organizer subunit of NOX2, significantly attenuated cognitive impairment and tau pathology in these mice. p47 phox deficiency decreased the activation of astrocytes but had no effect on Aβ levels and amyloid plaque formation in the brains of aged APP/PS1 mice, which displayed markedly increased expression of p47 phox in neurons and astrocytes. Cell culture studies found that neuronal p47 phox deletion attenuated okadaic acid-induced tau hyperphosphorylation at specific sites in primary cultures of neurons. CM from high glucose-treated WT astrocytes increased tau hyperphosphorylation in primary neurons, whereas this effect was absent from p47 phox -deficient astrocytes. Conclusions: These results suggest that p47 phox is associated with cognitive function and tau pathology in AD. p47 phox expressed in neurons contributes to tau hyperphosphorylation directly, while p47 phox in astrocytes affect tau hyperphosphorylation by activating astrocytes indirectly. Our results provide new insights into the role of NOX2 in AD and indicate that targeted inhibition of p47 phox may be a new strategy for the treatment of AD.
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Tau pathology is more associated with cognitive dysfunction than Aβ pathology, making tau a potential therapeutic target.
“Tau has received increasing attention as a potential therapeutic target, since evidence indicates that tau pathology is more associated with cognitive dysfunction.”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [13]
Increasing evidence demonstrates that cognitive dysfunction and disease severity are more related to tau pathology.
“Increasing evidence demonstrates that the cognitive dysfunction and severity of the disease are more related to tau pathology [11–14].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [13]
p47phox expression in neurons contributes to tau hyperphosphorylation directly, while p47phox in astrocytes affects tau hyperphosphorylation by activating astrocytes indirectly.
“The expression of p47phox in neurons contributes to tau hyperphosphorylation directly, while p47phox in astrocytes affects tau hyperphosphorylation by activating astrocytes indirectly [13].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [13]
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Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation
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- Authors
- Gong, P., Chen, Y.-Q., Lin, A.-H., Zhang, H.-B., Zhang, Y., Ye, R. D., & Yu, Y.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Chinese University of Hong Kong (HK)
- Corresponding author
- Ye, Richard D.
- Yu, Yang
- Venue
- Alzheimer's Research & Therapy
- Published
- 2020-11-12
- Volume
- 12
- Issue
- 1
- Pages
- 146-146
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC7659091
- OpenAlex
- W3100757084
- Cited by
- 29
- References
- 62
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 6 · 2023: 5 · 2021: 6
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81870835, 81571027, 31270941)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- p47phox, NADPH oxidase, NOX2, Alzheimer's disease, tau hyperphosphorylation, cognitive impairment, amyloid plaques, APP/PS1 mice, astrocyte activation, high glucose, okadaic acid, NCF1, oxidative stress, memory loss, astrocyte-neuron interaction
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Amyloid beta-Peptides, tau Proteins, NADPH Oxidases, Mice, Cognitive Dysfunction
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