摘要
背景:阿尔茨海默病(AD)是一种渐进性的神经退行性疾病,特点是明确的病理变化包括大脑淀粉样斑块、神经纤维缠结和慢性炎症的存在。目的:脑渗透BET布罗莫结构域抑制剂JQ1已被证明是调节在体外和体内的炎症反应,但其在阿尔茨海默病的治疗潜力是目前未知。方法:三个月大的3xTG小鼠皮下注射每日一次用JQ1(50毫克/公斤)或赋形剂15周。在治疗结束后的学习和记忆进行了评估使用修改后的巴尼斯迷宫和Y迷宫行为测试。从大脑和其他器官组织收集的分子评价神经tau病理和β-淀粉样蛋白。结果:在大脑中JQ1治疗减少脾肿大和炎症反应,我们观察到在小鼠的炎症调节Il-1b, Il-6, Tnfa, Ccl2, Nos2和 Ptgs2的表达减少。此外,JQ1处理的小鼠表现出Ser396在大脑皮质和海马tau蛋白水平减少,而总额tau蛋白磷酸化水平不受影响。另一方面,在七个月3xTG小鼠上JQ1没有改善学习和记忆障碍。结论:综上所述,我们的数据表明,BET 布罗莫结构域抑制剂被认为是在用于治疗以神经炎症为特征的神经系统疾病。
关键词: 阿尔茨海默病,星形胶质细胞,小胶质细胞的炎症反应,神经炎症,布罗莫结构域JQ1,脾肿大。
Current Alzheimer Research
Title:The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease
Volume: 13 Issue: 9
Author(s): Marco Magistri, Dmitry Velmeshev, Madina Makhmutova, Prutha Patel, Gregory C. Sartor, Claude-Henry Volmar, Claes Wahlestedt and Mohammad Ali Faghihi
Affiliation:
关键词: 阿尔茨海默病,星形胶质细胞,小胶质细胞的炎症反应,神经炎症,布罗莫结构域JQ1,脾肿大。
摘要: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation. Objective: The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown. Method: Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid β. Results: JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro-inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month-old 3xTg mice. Conclusion: Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation.
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Marco Magistri, Dmitry Velmeshev, Madina Makhmutova, Prutha Patel, Gregory C. Sartor, Claude-Henry Volmar, Claes Wahlestedt and Mohammad Ali Faghihi , The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease, Current Alzheimer Research 2016; 13 (9) . https://dx.doi.org/10.2174/1567205013666160427101832
DOI https://dx.doi.org/10.2174/1567205013666160427101832 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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