NADPH oxidase 2 as a potential therapeutic target for protection against cognitive deficits following systemic inflammation in mice

Huang, Wan Yu; Liu, Ko Hung; Lin, Shankung; Chen, Ting Yu; Tseng, Chien Yu; Chen, Hsuan Ying; Wu, Hsiang Ling

doi:10.1016/j.bbi.2019.12.006

Cited by 38 publications

(27 citation statements)

References 66 publications

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“…These results suggest that p47 phox participates in the activation of astrocytes in AD mice. In addition, studies have found that p47 phox is highly expressed in microglia and NADPH oxidase plays a vital role in microglia activation [37]. Thus, we detected the effect of p47 phox on microglia activation in APP/PS1 mice.…”

Section: P47 Phox Expressed In Astrocytes Affects Tau Phosphorylationmentioning

confidence: 79%

“…We found that microglia are activated in APP/PS1 mice to a certain extent, and p47 phox deficiency inhibits the activation of microglia. Studies have shown that p47 phox is highly expressed in microglia and NADPH oxidase plays a key role in microglia activation [37]. The activation of microglia is related to the pathology of tau [24,[49][50][51][52].…”

Section: Discussionmentioning

confidence: 99%

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p47phox deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD

et al. 2020

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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 p47phox-deficient mice (with deletion of the gene of neutrophil cytosolic factor 1, Ncf1) and/or in p47phox-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, p47phox 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 p47phox, the organizer subunit of NOX2, significantly attenuated cognitive impairment and tau pathology in these mice. p47phox 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 p47phox in neurons and astrocytes. Cell culture studies found that neuronal p47phox 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 p47phox-deficient astrocytes. Conclusions These results suggest that p47phox is associated with cognitive function and tau pathology in AD. p47phox expressed in neurons contributes to tau hyperphosphorylation directly, while p47phox 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 p47phox may be a new strategy for the treatment of AD.

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Section: P47 Phox Expressed In Astrocytes Affects Tau Phosphorylationmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

p47phox deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD

et al. 2020

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“…GFAP-IL6 mice show age-dependent reductions in cerebellar volume and PSD-95 protein levels from 14 months of age, which are not evident at 6 months (Gyengesi et al, 2019). It is possible that the age-dependent reduction in PSD-95 contributes to the impaired recall in the BM in GFAP-IL6 mice, as other manipulations which induce inflammation and reduce spatial memory (e.g., lipopolysaccharide administration) also reduce PSD-95 protein levels (Liu et al, 2018;Huang et al, 2020). Cerebellar volume loss may not contribute to spatial recall impairment in GFAP-IL6 mice, as a mouse model of AD which shows enhanced inflammation as well as spatial learning and memory deficits actually shows increased cerebellar volume (Badea et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Spatial Memory and Microglia Activation in a Mouse Model of Chronic Neuroinflammation and the Anti-inflammatory Effects of Apigenin

et al. 2021

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Chronic neuroinflammation characterized by microglia reactivity is one of the main underlying processes in the initiation and progression of neurodegenerative diseases such as Alzheimer’s disease. This project characterized spatial memory during healthy aging and prolonged neuroinflammation in the chronic neuroinflammatory model, glial fibrillary acidic protein-interleukin 6 (GFAP-IL6). We investigated whether chronic treatment with the natural flavonoid, apigenin, could reduce microglia activation in the hippocampus and improve spatial memory. GFAP-IL6 transgenic and wild-type-like mice were fed with apigenin-enriched or control chow from 4 months of age and tested for spatial memory function at 6 and 22 months using the Barnes maze. Brain tissue was collected at 22 months to assess microgliosis and morphology using immunohistochemistry, stereology, and 3D single cell reconstruction. GFAP-IL6 mice showed age-dependent loss of spatial memory recall compared with wild-type-like mice. Chronic apigenin treatment decreased the number of Iba-1+ microglia in the hippocampus of GFAP-IL6 mice and changed microglial morphology. Apigenin did not reverse spatial memory recall impairment in GFAP-IL6 mice at 22 months of age. GFAP-IL6 mice may represent a suitable model for age-related neurodegenerative disease. Chronic apigenin supplementation significantly reduced microglia activation, but this did not correspond with spatial memory improvement in the Barnes Maze.

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“…Recent studies have demonstrated that NOX2 contributes to glial activation with a subsequent reduction in the expression of BDNF, synaptic dysfunction, and cognitive deficits after systemic inflammation in an LPS-injected mouse model. They provide evidence that NOX2 might be a promising pharmacological target to protect against synaptic dysregulation and cognitive impairment following systemic inflammation [ 164 ].…”

Section: Molecular Mechanisms Of Neuronal Toxicity In Saementioning

confidence: 99%

Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation

et al. 2021

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Frequently underestimated, encephalopathy or delirium are common neurological manifestations associated with sepsis. Brain dysfunction occurs in up to 80% of cases and is directly associated with increased mortality and long-term neurocognitive consequences. Although the central nervous system (CNS) has been classically viewed as an immune-privileged system, neuroinflammation is emerging as a central mechanism of brain dysfunction in sepsis. Microglial cells are major players in this setting. Here, we aimed to discuss the current knowledge on how the brain is affected by peripheral immune activation in sepsis and the role of microglia in these processes. This review focused on the molecular pathways of microglial activity in sepsis, its regulatory mechanisms, and their interaction with other CNS cells, especially with neuronal cells and circuits.

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NADPH oxidase 2 as a potential therapeutic target for protection against cognitive deficits following systemic inflammation in mice

Cited by 38 publications

References 66 publications

p47phox deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD

p47phox deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD

Spatial Memory and Microglia Activation in a Mouse Model of Chronic Neuroinflammation and the Anti-inflammatory Effects of Apigenin

Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation

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