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

• Published in: Alzheimer's research & therapy 2020-11, Vol.12 (1), p.1-146, Article 146
• Main Authors: Gong, Ping, Chen, Yan-qing, Lin, Ai-hua, Zhang, Hai-bo, Zhang, Yan, Ye, Richard D, Yu, Yang
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Antibodies; Biotechnology; Cognition; Cognitive ability; Dementia; Development and progression; Females; Genetic aspects; Genotype & phenotype; Health aspects; Hypotheses; Laboratory animals; Males; Ncf1; Nicotinamide adenine dinucleotide phosphate; Nicotinamide adenine dinucleotide phosphate oxidase; NOX2; Oxidases; Oxidative stress; p47phox; Pathogenesis; Pathology; Physiological aspects; Proteins; Rodents; Tau proteins; Transgenic animals
• ISSN: 1758-9193; 1758-9193
• DOI: 10.1186/s13195-020-00714-2

Background Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive impairment. The aggregation of amyloid [beta] (A[beta]) and hyperphosphorylated tau protein are two major pathological features of AD. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) has been indicated in A[beta] 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.sup.phox-deficient mice (with deletion of the gene of neutrophil cytosolic factor 1, Ncf1) and/or in p47.sup.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. A[beta] levels, amyloid plaques, p47.sup.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.sup.phox, the organizer subunit of NOX2, significantly attenuated cognitive impairment and tau pathology in these mice. p47.sup.phox deficiency decreased the activation of astrocytes but had no effect on A[beta] levels and amyloid plaque formation in the brains of aged APP/PS1 mice, which displayed markedly increased expression of p47.sup.phox in neurons and astrocytes. Cell culture studies found that neuronal p47.sup.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.sup.phox-deficient astrocytes. Conclusions These results suggest that p47.sup.phox is associated with cognitive function and tau pathology in AD. p47.sup.phox expressed in neurons contributes to tau hyperphosphorylation directly, while p47.sup.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.sup.phox may b