p47(phox) deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD.
p47(phox) deficiency improves cognitive impairment and attenuates tau hyperphosphorylation in mouse models of AD.
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p47phox 缺乏可改善 AD 小鼠模型中的认知障碍并减弱 tau 过度磷酸化
DOI：
10.1186/s13195-020-00714-2
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发表时间：
2020-11-12
期刊：
影响因子：
--
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Gong P;Chen YQ;Lin AH;Zhang HB;Zhang Y;Ye RD;Yu Y
阿尔茨海默病（Alzheimer's disease，AD）是一种以进行性记忆丧失和认知功能障碍为特征的疾病。β淀粉样蛋白（Aβ）聚集和tau蛋白过度磷酸化是AD的两个主要病理特征。烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NADPH氧化酶，NOX）在Aβ病理学中已被证实;然而，它是否以及如何影响tau病理学尚不清楚。在APP/PS1转基因小鼠与p47 phox缺陷小鼠（缺失中性粒细胞胞质因子1，Ncf 1基因）交配和/或在p47 phox缺陷小鼠接受脑室内（ICV）注射链脲佐菌素（STZ）中，研究了NOX 2在认知功能，淀粉样斑块形成和tau蛋白过度磷酸化中的作用。采用Morris水迷宫、旋转棒试验、旷场试验和高架十字迷宫等方法评价小鼠的认知和非认知功能。使用免疫荧光染色、ELISA和/或Western印迹法评价Aβ水平、淀粉样蛋白斑块、p47 phox表达和星形胶质细胞活化。用冈田酸或来自高糖刺激的原代星形胶质细胞的条件培养基（CM）处理培养的原代神经元细胞。使用蛋白质印迹和免疫荧光染色确定tau病理学的改变。缺失编码p47 phox（NOX 2的组织者亚基）的基因显著减轻了这些小鼠的认知障碍和tau病理学。老年APP/PS1小鼠脑内p47 phox的表达明显增加，但对Aβ水平和淀粉样斑块的形成无影响。细胞培养研究发现，神经元p47 phox缺失减弱冈田酸诱导的tau蛋白过度磷酸化，在特定的网站在原代培养的神经元。高糖处理的WT星形胶质细胞的CM增加了原代神经元中tau的过度磷酸化，而这种作用在p47 phox缺陷的星形胶质细胞中不存在。这些结果表明，p47 phox与AD的认知功能和tau病理学相关。神经元中表达的p47 phox直接参与tau蛋白的过度磷酸化，而星形胶质细胞中表达的p47 phox通过激活星形胶质细胞间接影响tau蛋白的过度磷酸化。我们的研究结果为NOX 2在AD中的作用提供了新的见解，并表明靶向抑制p47 phox可能是治疗AD的新策略。
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. 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. 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. 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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影响因子：
3.1
作者：
Elder, Gregory A.;Sosa, Miguel A. Gama;De Gasperi, Rita;Dickstein, Dara L.;Hof, Patrick R.
通讯作者：
Hof, Patrick R.
影响因子：
11.4
作者：
Cheignon C;Tomas M;Bonnefont-Rousselot D;Faller P;Hureau C;Collin F
通讯作者：
Collin F
血清淀粉样蛋白 A 抑制 LPS 诱导的 tau 过度磷酸化
影响因子：
9.3
作者：
Liu J;Wang D;Li SQ;Yu Y;Ye RD
通讯作者：
Ye RD
DOI：
10.1186/1478-811x-10-35
发表时间：
2012-11-23
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Lin CC;Hsieh HL;Shih RH;Chi PL;Cheng SE;Chen JC;Yang CM
通讯作者：
Yang CM
影响因子：
5.3
作者：
Choi, SH;Lee, DY;Jin, BK
通讯作者：
Jin, BK