Effect of Danggui Shaoyaosan on Improvement of Cognitive Ability of SAMP8 Mice and Its Mechanism via Regulating Ubiquitin Proteasome Pathway

CHEN Yunhui; XIA Jun; HUAI Wenying; LIU Dan; ZHANG Tiane; LI Yan; XIE Yongmei; TANG Songqi; YOU Yu; PENG Wei

doi:10.13422/j.cnki.syfjx.20211107

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Effect of Danggui Shaoyaosan on Improvement of Cognitive Ability of SAMP8 Mice and Its Mechanism via Regulating Ubiquitin Proteasome Pathway

更新时间：2022-11-17

- Effect of Danggui Shaoyaosan on Improvement of Cognitive Ability of SAMP8 Mice and Its Mechanism via Regulating Ubiquitin Proteasome Pathway
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 28, Issue 24, Pages: 8-16(2022)
- 作者机构：
  
  1.成都中医药大学，成都 611137
  2.四川大学，成都 610041
  3.路易斯维尔大学，美国路易斯维尔 40202
  4.海南医学院，海口 570102
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20211107
  CLC： R2-0;R22;R285.5;R289;R33
- Received：04 February 2021，
  
  Published Online：14 April 2021，
  
  Published：20 December 2022
- 稿件说明：
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陈云慧,夏军,淮文英等.当归芍药散调控泛素-蛋白酶体途径改善SAMP8小鼠认知能力的作用及其机制[J].中国实验方剂学杂志,2022,28(24):8-16.

CHEN Yunhui,XIA Jun,HUAI Wenying,et al.Effect of Danggui Shaoyaosan on Improvement of Cognitive Ability of SAMP8 Mice and Its Mechanism via Regulating Ubiquitin Proteasome Pathway[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(24):8-16.
陈云慧,夏军,淮文英等.当归芍药散调控泛素-蛋白酶体途径改善SAMP8小鼠认知能力的作用及其机制[J].中国实验方剂学杂志,2022,28(24):8-16. DOI： 10.13422/j.cnki.syfjx.20211107.

CHEN Yunhui,XIA Jun,HUAI Wenying,et al.Effect of Danggui Shaoyaosan on Improvement of Cognitive Ability of SAMP8 Mice and Its Mechanism via Regulating Ubiquitin Proteasome Pathway[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(24):8-16. DOI： 10.13422/j.cnki.syfjx.20211107.

摘要

目的

探讨当归芍药散（DSS）调控泛素-蛋白酶体途径（UPP）改善SAMP8阿尔茨海默病（AD）模型小鼠认知能力的作用机制。

方法

15只SAMR1小鼠为正常组，60只SAMP8小鼠随机分为模型组及DSS高、中、低剂量组（57.6、28.8、14.4 g·kg

-1

·d

-1

），连续灌胃给药8周。Morris水迷宫实验测试定位航行与空间探索能力；苏木素-伊红（HE）染色法检测海马CA1区神经元病理结构改变；免疫组化法（IHC）和酶联免疫吸附测定法（ELISA）检测海马

淀粉样蛋白（A

）和磷酸化（p）-Tau蛋白含量，实时荧光定量聚合酶链式反应（Real-time PCR）和蛋白免疫印迹法（Western blot）检测海马组织泛素（Ub）、泛素连接酶E3（E3）、26S蛋白酶体、泛素羧基端水解酶1（UCHL1）、UCHL3 mRNA和蛋白表达。

结果

与正常组比较，模型组小鼠逃避潜伏期延长（

0.05），穿越平台象限次数和平台象限停留百分比减少（

0.05）；CA1区神经元明显减少、胞体聚缩；

-淀粉样前体蛋白（

-APP）和p-Tau阳性细胞数量明显增多（

0.05）；A

和p-Tau蛋白水平升高（

0.05）；Ub mRNA和蛋白表达升高（

0.05）；E3、26S蛋白酶体、UCHL1、UCHL3 mRNA和蛋白表达下降（

0.05）。与模型组比较，DSS高、中剂量组逃避潜伏期缩短（

0.05），穿越平台象限次数和停留百分比增加（

0.05）；DSS各剂量组CA1病理改变明显改善；各剂量组

-APP及中、低剂量组p-Tau阳性染色细胞数量减少（

0.05）；各剂量组A

及p-Tau蛋白水平下降（

0.05）；各剂量组 Ub mRNA表达降低（

0.05），高、中剂量组26S、E3、UCHL3 mRNA表达水平升高（

0.05），中剂量组UCHL1 mRNA表达升高（

0.05）；各剂量组Ub蛋白表达降低，高、中剂量组26S、E3、UCHL1+3蛋白表达升高（

0.05）。

结论

DSS可改善SAMP8小鼠认知能力，其机制可能与降低UPP途径中Ub及升高E3、26S、UCHL1、UCHL3的表达，减少A

和p-Tau异常沉积有关。

Abstract

Objective

To investigate the mechanism of Danggui Shaoyaosan （DSS） in the improvement of the cognitive ability of SAMP8 mice with Alzheimer's disease （AD） via regulating the ubiquitin-proteasome pathway （UPP）.

Method

Fifteen SAMR1 mice were used as a normal group， and 60 SAMP8 mice were randomly divided into a model group and DSS high， medium， and low-dose groups （57.6， 28.8， and 14.4 g·kg

-1

·d

-1

）， with 15 mice in each group. Intragastric administration was conducted for eight continuous weeks. Place navigation and spatial capacity were evaluated by Morris water maze. Pathological structure changes in neurons in the hippocampal CA1 area was detected by hematoxylin-eosin （HE） staining. The protein expression levels of hippocampal

-amyloid protein（A

） and phosphorylation（p）-Tau were determined by immunohistochemical staining （IHC） and enzyme-linked immunosorbent assay （ELISA）， and the mRNA and protein expression levels of hippocampal ubiquitin （Ub）， ubiquitin ligase E3 （E3）， 26S proteasome， ubiquitin carboxyl terminal hydrolase-1 （UCHL1）， and UCHL3 were determined by real-time fluorescent quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively.

Result

As compared with the normal group， the escape latency was prolonged in the model group （

0.05） with the reduced number of crossing platform quadrants and time ratio in the platform quadrant （

0.05）. The model group decreased neurons and condensed cell bodies in the CA1 area， and increased

-amyloid precursor protein （

-APP） and p-Tau positive cells （

0.05）. In the model group， the protein expression levels of A

and p-Tau were increased （

0.05）， the mRNA and protein expression levels of Ub were increased （

0.05）， and the mRNA and protein expression levels of E3， 26S proteasome， UCHL1， and UCHL3 were decreased （

0.05）. As compared with the model group， the escape latency was shortened in the DSS high and medium-dose groups （

0.05） with an increased number of crossing platform quadrants and residence time ratio （

0.05）. The pathological changes in CA1 of each DSS group were significantly improved， and the number of

-APP positive staining cells decreased （

0.05）. The number of p-Tau positive staining cells decreased in the DDS medium and low-dose groups （

0.05）. The protein expression levels of A

and p-Tau in each DDS group decreased （

0.05）， and the mRNA expression level of Ub in each group decreased （

0.05）. The mRNA expression levels of 26S， E3， and UCHL3 in the DDS high and medium-dose groups increased （

0.05）， and the mRNA expression level of UCHL1 in the DDS medium-dose group increased （

0.05）. The protein expression level of Ub in each DDS group decreased， and the protein expression levels of 26S， E3， UCHL1+3 in the DDS high and medium-dose groups increased （

0.05）.

Conclusion

DSS can improve the cognitive ability of SAMP8 mice， and its mechanism may be related to the reduction of the abnormal deposition of A

and p-Tau via decreasing the expression of Ub and increasing that of E3， 26S， UCHL1， and UCHL3 in the UPP.

关键词

Keywords

references

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