山茱萸环烯醚萜苷对APP/PS1/Tau三转基因小鼠脑内病理变化的影响

doi:10.3969/j.issn.1006-7795.2019.04.018

首都医科大学学报 ›› 2019, Vol. 40 ›› Issue (4): 588-595.doi: 10.3969/j.issn.1006-7795.2019.04.018

• 神经系统退行性疾病的基础研究 • 上一篇下一篇

山茱萸环烯醚萜苷对APP/PS1/Tau三转基因小鼠脑内病理变化的影响

杨翠翠, 包训杰, 张丽, 李雅莉, 李林, 张兰

首都医科大学宣武医院药学部北京市神经药物工程技术研究中心北京脑重大疾病研究院神经变性病教育部重点实验室, 北京 100053

收稿日期:2019-05-15 出版日期:2019-07-21 发布日期:2019-07-19
通讯作者: 张兰 E-mail:lanizhg@126.com
基金资助:
国家自然科学基金（81874351，81703729），北京市自然科学基金（7164315），北京市高层次卫生技术人才计划（2014－2－014）。

Effects of cornel iridoid glycoside on Alzheimer's disease-associated neuropathology in APP/PS1/Tau transgenic mice

Yang Cuicui, Bao Xunjie, Zhang Li, Li Yali, Li Lin, Zhang Lan

Department of Pharmacy, Xuanwu Hospital, Capital Medical University;Beijing Engineering Research Center for Nerve System Drugs;Beijing Institute for Brain Disorders;Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China

Received:2019-05-15 Online:2019-07-21 Published:2019-07-19
Supported by:
This study was supported by National Natural Science Foundation of China (81874351,81703729), Natural Science Foundation of Beijing (7164315),Beijing High-level Health and Technical Personal Plan(2014-2-014).

摘要/Abstract

摘要： 目的利用APP/PS1/Tau三转基因（3×Tg）模型小鼠，观察山茱萸环烯醚萜苷（cornel iridoid glycoside，CIG）对小鼠脑内多种病理变化的影响。方法 16月龄3×Tg模型小鼠灌胃给予100或200 mg·kg^－1·d^－1 CIG至18月龄。采用刚果红染色法观察3×Tg小鼠海马中老年斑沉积情况；Western blotting方法检测Tau蛋白在Thr212及Thr217位点的磷酸化水平；应用免疫组织化学法观察小鼠海马中脑源性神经营养因子（brain derived neurotrophic factor，BDNF）的表达和分布；并采用实时荧光定量聚合酶链式反应法（quantitative real-time polymerase chain reaction，qRT-PCR）检测各组小鼠BDNF转录水平变化；应用尼氏染色法观察小鼠海马中尼氏小体的变化。结果 18月龄模型组小鼠与对照组相比，Aβ淀粉样斑块沉积明显增加，而给予CIG 100或200 mg·kg^－1·d^－1均能不同程度降低脑内斑块负荷；模型组小鼠Tau蛋白在Thr217位点的磷酸化水平明显升高，而在Thr212位点的磷酸化水平无明显升高，CIG治疗组能明显拮抗Tau蛋白在Thr217位点的过度磷酸化。模型组小鼠海马BDNF蛋白及mRNA的水平均降低，CIG能够明显恢复BDNF蛋白及mRNA的含量；模型组小鼠海马内尼氏小体数量减少、染色变浅、排列散乱，CIG有增高尼氏体数量的趋势。结论 CIG能够减少Aβ在脑内的沉积，Tau蛋白异常过度磷酸化，恢复BDNF在脑内的表达，并且保护神经元。

关键词: 山茱萸环烯醚萜苷, Aβ, Tau, 神经营养因子, 阿尔茨海默病

Abstract: Objective To observe the effects of Cornel iridoid glycoside (CIG) on pathology in the brain of 3×Tg mice. Methods The APP/PS1/Tau (3×Tg) mice were intragastrically administered with CIG (100 mg/kg, 200 mg/kg) once a day for 2 months. Congo red staining was used to observe the number and distribution of senile plaque in hippocampus. Western blotting was used to observe the expression of tau phosphorylation at Thr212 and Thr217. Immunohistochemistry and qRT-PCR were used to detect protein and transcription level of brain derived neurotrophic factor (BDNF). Nissl staining was used to observe the number of Nissl's body in hippocampus. Results Compared with the control group, the Aβ amyloid plaque deposition increased significantly in the 18-month-old model group, while 100 or 200 mg·kg^-1·d^-1 CIG treatment could reduce the plaque burden in the brain. The phosphorylation level of tau at Thr217 was significantly increased in the model group, while that at Thr212 was not significantly elevated. CIG treatment significantly antagonized the hyperphosphorylation of tau at Thr217. In the model group, the protein and mRNA levels of BDNF in hippocampus were decreased, and CIG could significantly restore the protein and mRNA levels of BDNF. CIG treatment could increase the number of Nissl's body in the brain. Conclusion CIG could reduce the deposition of Aβ in the brain, abnormal hyperphosphorylation of tau protein, restore the expression of BDNF in the brain, and protect neurons.

Key words: cornel iridoid glycoside, Aβ, Tau, brain derived neurotrophic factor (BDNF), Alzheimer's disease

中图分类号:

R592

杨翠翠, 包训杰, 张丽, 李雅莉, 李林, 张兰. 山茱萸环烯醚萜苷对APP/PS1/Tau三转基因小鼠脑内病理变化的影响[J]. 首都医科大学学报, 2019, 40(4): 588-595.

Yang Cuicui, Bao Xunjie, Zhang Li, Li Yali, Li Lin, Zhang Lan. Effects of cornel iridoid glycoside on Alzheimer's disease-associated neuropathology in APP/PS1/Tau transgenic mice[J]. Journal of Capital Medical University, 2019, 40(4): 588-595.

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山茱萸环烯醚萜苷对APP/PS1/Tau三转基因小鼠脑内病理变化的影响

Effects of cornel iridoid glycoside on Alzheimer's disease-associated neuropathology in APP/PS1/Tau transgenic mice

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