中国组织工程研究

中国组织工程研究 ›› 2025, Vol. 29 ›› Issue (6): 1176-1182.doi: 10.12307/2025.323

• 组织构建实验造模 experimental modeling in tissue construction • 上一篇    下一篇

阿戈美拉汀缓解APP/PS1转基因小鼠焦虑及抑郁样行为的机制

李  甜1，任俞桦2，高艳萍2，苏  强1，2   

  1. 1山西医科大学基础医学院生理学系，细胞生理学教育部重点实验室，细胞生理学山西省重点实验室，山西省太原市  030001；2山西医科大学汾阳学院医学检验系，山西省汾阳市  032200
  • 收稿日期:2024-02-07 接受日期:2024-04-17 出版日期:2025-02-28 发布日期:2024-06-21
  • 通讯作者: 李甜，讲师，山西医科大学基础医学院生理学系，细胞生理学教育部重点实验室，细胞生理学山西省重点实验室，山西省太原市030001 通讯作者：苏强，技师，山西医科大学基础医学院生理学系，细胞生理学教育部重点实验室，细胞生理学山西省重点实验室，山西省太原市030001；山西医科大学汾阳学院医学检验系，山西省汾阳市 032200
  • 作者简介:李甜，女，1991年生，山西省太原市人，汉族，博士，讲师，主要从事阿尔茨海默病的防治研究。
  • 基金资助:
    国家自然科学基金委员会青年科学基金项目(82301631)，项目负责人：李甜；山西省科技厅山西省基础研究自然科学研究青年项目(20210302124086)，项目负责人：李甜

Mechanism of agomelatine alleviating anxiety- and depression-like behaviors in APP/PS1 transgenic mice #br#
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Li Tian1, Ren Yuhua2, Gao Yanping2, Su Qiang1, 2   

  1. 1Department of Physiology, School of Basic Medicine; Key Laboratory of Cellular Physiology, Ministry of Education; Shanxi Key Laboratory of Cell Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China; 2Department of Medical Laboratory, Fenyang College of Shanxi Medical University, Fenyang 032200, Shanxi Province, China
  • Received:2024-02-07 Accepted:2024-04-17 Online:2025-02-28 Published:2024-06-21
  • Contact: Li Tian, Department of Physiology, School of Basic Medicine; Key Laboratory of Cellular Physiology, Ministry of Education; Shanxi Key Laboratory of Cell Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China Co-corresponding author: Su Qiang, Technician, Department of Physiology, School of Basic Medicine; Key Laboratory of Cellular Physiology, Ministry of Education; Shanxi Key Laboratory of Cell Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China; Department of Medical Laboratory, Fenyang College of Shanxi Medical University, Fenyang 032200, Shanxi Province, China
  • About author:Li Tian, PhD, Lecturer, Department of Physiology, School of Basic Medicine; Key Laboratory of Cellular Physiology, Ministry of Education; Shanxi Key Laboratory of Cell Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
  • Supported by:
    the National Natural Science Foundation of China, No. 82301631 (to LT); the Natural Science Research Youth Program of Shanxi Provincial Department of Science and Technology, No. 20210302124086 (to LT)

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摘要：




文题释义：
阿尔茨海默病：是一种不可逆的进行性神经退行性疾病，是最常见的痴呆类型，该病脑内病理特征包括β-淀粉样蛋白沉积形成的老年斑、过度磷酸化tau蛋白聚集形成的神经原纤维缠结和大量神经元丧失，最终导致脑萎缩。阿尔茨海默病的临床表现主要为认知和记忆功能障碍，同时伴有神经精神症状，如焦虑和抑郁。
阿戈美拉汀：是一种褪黑素类似物，具有激动褪黑素受体(MT1和MT2受体)和拮抗5-HT2C受体的双重效应，临床上主要用来治疗重度抑郁症，已有研究证实阿戈美拉汀对改善睡眠和认知也有积极的作用。

背景：阿戈美拉汀在临床上用于治疗焦虑、抑郁等相关精神行为异常。前期研究证实，阿戈美拉汀能够有效缓解阿尔茨海默病模型小鼠的认知行为、海马突触可塑性及脑病理特征，然而阿戈美拉汀能否改善阿尔茨海默病模型小鼠的焦虑和抑郁样行为仍不清楚。
目的：探究阿戈美拉汀对APP/PS1(阿尔茨海默病)转基因小鼠焦虑和抑郁样行为的改善效应及分子机制。
方法：①将18只APP/PS1转基因小鼠随机分为模型对照组(n=9)、模型干预组(n=9)，将18只野生型小鼠随机分为对照组(n=9)、干预组(n=9)，模型干预组与干预组小鼠腹腔注射阿戈美拉汀10 mg/(kg·d)，连续注射31 d后进行高架十字迷宫、强迫游泳行为学实验与海马组织mRNA测序。②取小鼠海马神经元细胞株(HT22)、脑微血管内皮细胞株(bEnd.3)，分别分4组培养：空白组不加入任何药物，药物组加入20 µmol/L阿戈美拉汀，模型组加入10 µmol/L β-淀粉样蛋白1-42，实验组加入10 µmol/L β-淀粉样蛋白1-42+20 µmol/L阿戈美拉汀，培养24 h后，免疫印迹检测HT22细胞S416p-tau和S9p-GSK3β的蛋白表达，免疫印迹检测bEnd.3细胞低密度脂蛋白受体相关蛋白1、糖基化终产物受体的蛋白表达。
结果与结论：①在高架十字迷宫实验中，模型对照组小鼠的探索开放臂时间与开放臂进入次数均少于对照组(P < 0.05)，模型干预组小鼠的探索开放臂时间与开放臂进入次数均多于模型对照组(P < 0.05)；在强迫游泳测试中，模型对照组小鼠的不动时间长于对照组(P < 0.05)，模型干预组小鼠的不动时间短于模型对照组(P < 0.05)；海马组织mRNA测序显示，阿戈美拉汀可以增强APP/PS1小鼠海马区低密度脂蛋白受体相关蛋白1的表达。②免疫印迹检测显示，模型组HT22细胞S416p-tau蛋白表达高于空白组(P < 0.05)，实验组HT22细胞S416p-tau蛋白表达低于模型组(P < 0.05)，药物组HT22细胞S9p-GSK3β蛋白表达高于空白组(P < 0.05)，实验组HT22细胞S9p-GSK3β蛋白表达高于模型组(P < 0.05)，实验组bEnd.3细胞低密度脂蛋白受体相关蛋白1蛋白表达高于模型组(P < 0.05)。③结果表明，阿戈美拉汀可通过促进脑内β-淀粉样蛋白和tau的清除来缓解阿尔茨海默病小鼠的焦虑和抑郁样行为。
https://orcid.org/0000-0002-1444-832X(李甜)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 阿尔茨海默病, 阿戈美拉汀, APP/PS1转基因小鼠, 焦虑, 抑郁

Abstract:
BACKGROUND: Agomelatine is a clinically proven treatment for neuropsychiatric symptoms, such as anxiety and depression. Furthermore, our previous study has demonstrated that agomelatine ameliorates cognitive behaviors, hippocampal synaptic plasticity, and brain pathology in a mouse model of Alzheimer’s disease. However, it remains unclear whether agomelatine can improve anxiety and depression-like behaviors in Alzheimer’s disease model mice. 
OBJECTIVE: To investigate the improving effects of agomelatine on anxiety- and depression-like behaviors in APP/PS1 transgenic mice and its underlying molecular mechanisms. 
METHODS: (1) Eighteen APP/PS1 transgenic mice were randomly divided into model control group (n=9) and model intervention group (n=9). Another wild-type mice were randomized into control group (n=9) and intervention group (n=9). Model intervention group and intervention group were intraperitoneally injected with 10 mg/kg agomelatine per day for 31 continuous days. Behavioral experiments, including the elevated cross maze and forced swimming tests, and mRNA sequencing of the hippocampus were then performed. (2) Mouse hippocampal neuronal cell lines (HT22) and brain microvascular endothelial cell lines (bEnd.3) were cultured and divided into four groups: blank group without any drug, drug group with 20 µmol/L agomelatine, model group with 10 µmol/L β-amyloid 1-42, and experimental group with 10 µmol/L β-amyloid 1-42+20 µmol /L agomelatine. After 24 hours of incubation, protein expression of S416p-tau and S9p-GSK3β in HT22 cells was detected by immunoblotting, and protein expression of low-density lipoprotein receptor-related protein 1 and glycosylation end-product receptor in bEnd.3 cells was detected by immunoblotting.
RESULTS AND CONCLUSION: In the elevated plus maze test, the time spent in the open arms (P < 0.01) and the entries into open arms (P < 0.05) in the mice of model control group were evidently lower than those in the control group, whereas those were obviously increased in the model intervention group compared with the model control group (P < 0.05). Forced swimming test results showed that the immobile time exhibited a marked increase in the model control group compared with the control group (P < 0.05), but it was significantly decreased in the model intervention group compared with the model control group (P < 0.05). Hippocampal tissue mRNA sequencing showed that agomelatine enhanced the expression of low-density lipoprotein receptor-related protein 1 in the hippocampus of APP/PS1 mice. Western blot analysis revealed that the level of S416p-tau in HT22 cells was higher in the model group than the blank group (P < 0.05), while it was markedly decreased in the experimental group compared with the model group (P < 0.05); the level of S9p-GSK3β in HT22 cells was higher in the drug group than the blank group (P < 0.05) as well as higher in the experimental group than the model group (P < 0.05). Moreover, the expression of low-density lipoprotein receptor-related protein 1 in bEnd.3 cells was higher in the experimental group than the model group (P < 0.05). To conclude, agomelatine can alleviate anxiety- and depression-like behaviors in Alzheimer’s disease mice by promoting the clearance of β-amyloid and phosphorylated tau.

Key words: Alzheimer’s disease, agomelatine, APP/PS1 transgenic mice, anxiety, depression

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