中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2018, Vol. 13 ›› Issue (4): 709-716.doi: 10.4103/1673-5374.230299

• 原著:退行性病与再生 • 上一篇    下一篇

诱导阿尔茨海默病转基因模型小鼠脑内硬膜淋巴管生成：促进可溶性淀粉样β蛋白清除

  

  • 收稿日期:2018-01-29 出版日期:2018-04-15 发布日期:2018-04-15
  • 基金资助:

    中国国家自然科学基金项目（31371130， 31600836），广东省教育厅专项基金，广东省医学研究基金（2013-159），广东省医学科技研究项目（A2016273）

Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer’s disease

Ya-Ru Wen1, 2, Jun-Hua Yang1, 2, Xiao Wang1, 2, Zhi-Bin Yao1, 2   

  1. 1 Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China
    2 Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China
  • Received:2018-01-29 Online:2018-04-15 Published:2018-04-15
  • Contact: Zhi-Bin Yao, yao.zb@163.com
  • Supported by:

    The work was supported by the National Natural Science Foundation of China, No. 31371130 and 31600836; the Special Foundation of Education Department of Guangdong Province of China; the Medical Scientific Research Foundation of Guangdong Province of China, No. 2013-159; the Foundation of Medical Science and Technology Research of Guangdong Province of China, No. A2016273

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摘要：

脑内淀粉样β沉积是阿尔茨海默病的主要病理特征之一，目前药物治疗效果和存在严重的副作用令人不满意。硬脑膜淋巴管的发现为淀粉样β蛋白的清除提供了一种新的途径。实验拟探索促进硬脑膜淋巴管生成是否可以促进脑内淀粉样β蛋白清除的假设。首先通过100 ng/mL重组人血管内皮生长因子C干预体外培养的人淋巴内皮细胞，光镜观察证实血管内皮生长因子受体3的特异性配体重组人血管内皮生长因子C具有促进人淋巴内皮细胞成管的作用。然后在体内实验中对APP/PS1小鼠小脑延髓池注射200 μg/ mL重组人血管内皮生长因子C，每2d注射1次，共进行4次，免疫荧光染色检测结果发现阿尔茨海默病转基因模型小鼠硬脑膜淋巴管生成增多。继而，在注射重组人血管内皮生长因子C的1周后以ELISA分析发现脑内及脑脊液中多种可溶性淀粉样β蛋白水平降低，且小鼠在Morris水迷宫测试中空间认知水平得到恢复。此结果说明硬脑膜淋巴管生成上调可促进阿尔茨海默病模型小鼠脑内淀粉样β蛋白的清除，且血管内皮生长因子C/血管内皮生长因子受体3信号通路或可作为治疗阿尔茨海默病的靶点。

orcid:0000-0002-6538-0660(Ya-Ru Wen)
        0000-0001-8037-9644(Jun-Hua Yang)
        0000-0003-1613-9157(Zhi-Bin Yao)

 

关键词: 神经再生, 硬脑膜, 淋巴管生成, 淀粉样&beta, 蛋白, 阿尔茨海默病, 重组人血管内皮生长因子C, 淋巴管内皮细胞, 淋巴清除

Abstract:

Impaired amyloid-β clearance from the brain is a core pathological event in Alzheimer’s disease. The therapeutic effect of current pharmacotherapies is unsatisfactory, and some treatments cause severe side effects. The meningeal lymphatic vessels might be a new route for amyloid-β clearance. This study investigated whether promoting dural lymphangiogenesis facilitated the clearance of amyloid-β from the brain. First, human lymphatic endothelial cells were treated with 100 ng/mL recombinant human vascular endothelial growth factor-C (rhVEGF-C) protein. Light microscopy verified that rhVEGF-C, a specific ligand for vascular endothelial growth factor receptor-3 (VEGFR-3), significantly promoted tube formation of human lymphatic endothelial cells in vitro. In an in vivo study, 200 μg/mL rhVEGF-C was injected into the cisterna magna of APP/PS1 transgenic mice, once every 2 days, four times in total. Immunofluorescence staining demonstrated high levels of dural lymphangiogenesis in Alzheimer’s disease mice. One week after rhVEGF-C administration, enzyme-linked immunosorbent assay results showed that levels of soluble amyloid-β were decreased in cerebrospinal fluid and brain. The Morris water maze test demonstrated that spatial cognition was restored. These results indicate that the upregulation of dural lymphangiogenesis facilities amyloid-β clearance from the brain of APP/PS1 mice, suggesting the potential of the VEGF-C/VEGFR-3 signaling pathway as a therapeutic target for Alzheimer’s disease.

Key words: nerve regeneration, dura mater, lymphangiogenesis, amyloid-β, Alzheimer’s disease, recombinant human vascular endothelial growth factor-C, lymphatic endothelial cells, lymphatic clearance, neural regeneration