中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (9): 2019-2028.doi: 10.4103/1673-5374.366492

• 原著:退行性病与再生 • 上一篇    下一篇

抑制5-羟色胺受体3可缓解阿尔茨海默病小鼠模型的病理变化

  

  • 出版日期:2023-09-15 发布日期:2023-03-06
  • 基金资助:
    国家自然科学基金项目(81371213,81070987);上海市自然科学基金项目(21ZR1468400)

Inhibiting 5-hydroxytryptamine receptor 3 alleviates pathological changes of a mouse model of Alzheimer’s disease

Li-Fen Liu1, #, Yu-Tong Liu2, #, Dan-Dan Wu1, Jie Cheng1, Na-Na Li1, Ya-Ni Zheng1, Liang Huang1, 3, Qiong-Lan Yuan1, 3, *   

  1. 1Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China; 2Department of Radiology, University of Nebraska Medical Center, Omaha, NE, USA; 3Department of Human Anatomy, Histology & Embryology, Tongji University School of Medicine, Shanghai, China
  • Online:2023-09-15 Published:2023-03-06
  • Contact: Qiong-Lan Yuan, PhD, yqiongl@tongji.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81371213 and 81070987; and the Natural Science Foundation of Shanghai, No. 21ZR1468400 (all to QLY). 

摘要:

淀粉样蛋白β斑块是阿尔茨海默病的主要病理特征,然而尚不清楚哪种类型的神经元在阿尔茨海默病初始阶段产生淀粉样蛋白β。实验首先发现β淀粉样前体蛋白和早老素1转基因阿尔茨海默病模型小鼠和阿尔茨海默病患者的脑组织均存在高表达的5-羟色胺受体3亚单位A。为了解5-羟色胺受体3亚单位A中间神经元是否与位于中间神经元所在区域的β-淀粉样蛋白淀粉样斑产生有关,实验以免疫双标共聚焦显微镜观察可见,在阿尔茨海默病模型小鼠模型中,5-羟色胺受体3亚单位A阳性中间神经元聚集在淀粉样蛋白β斑块周围,且淀粉样蛋白β斑块附近的部分APP 阳性或β位点APP裂解酶-1阳性神经突与5-羟色胺受体3亚单位A中间神经元共定位,表明5-羟色胺受体3亚单位A强阳性中间神经元是产生β-淀粉样蛋白淀粉样斑的神经元之一。最后以5-羟色胺受体3阻断剂对5.0-5.5月龄阿尔茨海默病模型小鼠连续干预8周,可见小鼠的认知缺陷被部分逆转,β-淀粉样蛋白淀粉样斑和神经炎症显著减轻,且5-羟色胺受体3亚单位A表达也显著减少,钙调磷酸酶/活化T细胞核因子信号通路受到抑制。表明5-羟色胺受体3亚单位A阳性中间神经元可部分参与有助于阿尔茨海默病初始阶段淀粉样蛋白β的产生,且干扰5-羟色胺受体3亚单位A能够部分逆转阿尔茨海默病的病理变化。

https://orcid.org/0000-0001-6165-2107 (Qiong-Lan Yuan)

关键词: 阿尔茨海默病, 托烷司琼, 5-羟色胺受体3亚单位A, 中间神经元, 5-羟色胺受体3, 细胞内Ca2+, 钙调磷酸酶, 活化T细胞核因子, 淀粉样蛋白β, 斑块, 认知障碍, 转基因小鼠

Abstract: Extracellular amyloid beta (Aβ) plaques are main pathological feature of Alzheimer’s disease. However, the specific type of neurons that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown. In this study, we found that 5-hydroxytryptamin receptor 3A subunit (HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice (an Alzheimer’s disease model) and patients with Alzheimer’s disease. To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques, we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model. Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons. These results suggest that HTR3A -positive interneurons may partially contribute to the generation of Aβ peptides. We treated 5.0–5.5-month-old model mice with tropisetron, a HTR3 antagonist, for 8 consecutive weeks. We found that the cognitive deficit of mice was partially reversed, Aβ plaques and neuroinflammation were remarkably reduced, the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice. These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reverses the pathological changes of Alzheimer’s disease. 

Key words: 5-hydroxytryptamin receptor 3, Alzheimer’s disease, amyloid beta plaques, calcineurin, cognitive deficits, HTR3 interneurons, iCa2+, nuclear factor of activated T-cells, transgenic amyloid precursor protein and presenilin-1 mice, tropisetron