Age-related brain expression and regulation of the chemokine CCL4/MIP-1β in APP/PS1 double-transgenic mice.
Age-related brain expression and regulation of the chemokine CCL4/MIP-1β in APP/PS1 double-transgenic mice.
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APP/PS1 双转基因小鼠中趋化因子 CCL4/MIP-1β 的年龄相关大脑表达和调节。
DOI：
10.1097/nen.0000000000000060
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发表时间：
2014
影响因子：
3.2
通讯作者：
Rapp,PeterR
中科院分区：
文献类型：
--
作者：
Zhu,Min;Allard,JoanneS;Zhang,Yongqing;Perez,Evelyn;Spangler,EdwardL;Becker,KevinG;Rapp,PeterR
趋化因子CCL 4/MIP-1β的激活对HIV相关痴呆患者神经元完整性的有害影响已引起人们对CCL 4表达和调节在阿尔茨海默病中的潜在作用的关注。在这里，我们表明，CCL 4 mRNA和蛋白质在APPswe/PS1$E9（APP/PS1）双转基因小鼠，大脑淀粉样蛋白沉积模型的大脑中过表达;表达是最小的非转基因同窝出生或单突变对照组的大脑。CCL 4 mRNA和蛋白水平的增加与APP/PS1小鼠脑淀粉样蛋白-β（Aβ）水平的年龄相关性进展直接相关。我们还发现APP/PS 1小鼠脑中激活转录因子3（ATF 3）的表达显著增加，这与年龄相关的Aβ沉积和CCL 4呈正相关。染色质免疫沉淀-定量聚合酶链反应的结果证实，ATF 3结合到CCL 4基因的启动子区，与调节CCL 4转录的潜在作用一致。最后，APP/PS 1脑中ATF 3 mRNA表达的升高与ATF 3基因启动子区的低甲基化有关。这些观察提示了未来研究的可验证假设，即CCL 4过表达，部分受ATF 3基因低甲基化调节，可能有助于阿尔茨海默病中与淀粉样蛋白沉积相关的神经病理学进展。
The detrimental effect of activation of the chemokine CCL4/MIP-1β on neuronal integrity in patients with HIV-associated dementia has directed attention to the potential role of CCL4 expression and regulation in Alzheimer disease. Here, we show that CCL4 mRNA and protein are overexpressed in the brains ofAPPswe/PS1$E9(APP/PS1) double-transgenic mice, a model of cerebral amyloid deposition; expression was minimal in brains from nontransgenic littermates or single-mutant controls. Increased levels of CCL4 mRNA and protein directly correlated with the age-related progression of cerebral amyloid-β (Aβ) levels inAPP/PS1mice. We also found significantly increased expression of activating transcription factor 3 (ATF3), which was positively correlated with age-related Aβ deposition and CCL4 in the brains ofAPP/PS1mice. Results from chromatin immunoprecipitation-quantitative poly-merase chain reaction confirmed that ATF3 binds to the promoter region of theCCL4gene, consistent with a potential role in regulatingCCL4transcription. Finally, elevated ATF3 mRNA expression inAPP/PS1brains was associated with hypomethylation of theATF3gene promoter region. These observations prompt the testable hypothesis for future study that CCL4 overexpression, regulated in part by hypomethylation of theATF3gene, may contribute to neuropathologic progression associated with amyloid deposition in Alzheimer disease.