活体荧光成像结合金属离子检测研究乙基麦芽酚氧钒对阿尔茨海默病的作用

引用本文: 何志军, 白杨, 赵琼晖, 欧阳霈, 倪嘉缵, 刘琼, 甘文标, 张学记. 活体荧光成像结合金属离子检测研究乙基麦芽酚氧钒对阿尔茨海默病的作用. 分析化学, 2019, 47(10): 1680-1688. doi: 10.19756/j.issn.0253-3820.191426 [复制]

Citation: HE Zhi-Jun , BAI Yang , ZHAO Qiong-Hui , OUYANG Pei , NI Jia-Zuan , LIU Qiong , GAN Wen-Biao , ZHANG Xue-Ji . Application of in Vivo Fluorescence Imaging and Metal Ion Detection for Investigation of Bis (ethylmaltolato) Oxidovanadium(Ⅳ) on Alzheimer's Disease. Chinese Journal of Analytical Chemistry, 2019, 47(10): 1680-1688. doi: 10.19756/j.issn.0253-3820.191426 [复制]

活体荧光成像结合金属离子检测研究乙基麦芽酚氧钒对阿尔茨海默病的作用

何志军^1,, 白杨^2,, 赵琼晖^4,, 欧阳霈^1,, 倪嘉缵^1,, 刘琼^1,,, 甘文标^2,,, 张学记^3,,

¹ 深圳大学生命与海洋科学学院, 深圳 518055;

² 北京大学深圳研究生院, 深圳 518055;

³ 深圳大学医学部生物医学工程学院, 深圳 518055;

⁴ 深圳海关食品检验检疫技术中心, 深圳 518042

通讯作者: 刘琼, liuqiong@szu.edu.cn; 甘文标, wenbiao.gan@med.nyu.edu.cn; 张学记, zhangxueji@szu.edu.cn

收稿日期: 2019-07-20

基金项目: 本文系国家自然科学基金项目（Nos.21877081，21890740，21890742，21727815）、广东省重点领域研发计划（2018B030336001）和深圳市科技基金项目（JCYJ20180305124018343）资助

Application of in Vivo Fluorescence Imaging and Metal Ion Detection for Investigation of Bis (ethylmaltolato) Oxidovanadium(Ⅳ) on Alzheimer's Disease

HE Zhi-Jun ^1,, BAI Yang ^2,, ZHAO Qiong-Hui ^4,, OUYANG Pei ^1,, NI Jia-Zuan ^1,, LIU Qiong ^1,,, GAN Wen-Biao ^2,,, ZHANG Xue-Ji ^3,,

¹ College of Life Sciences & Oceanography, Shenzhen University, Shenzhen 518055, China;

² Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China;

³ College of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518055, China;

⁴ Shenzhen Food Inspection Center of CIQ, Shenzhen 518042, China

Corresponding author: LIU Qiong , liuqiong@szu.edu.cn; GAN Wen-Biao , wenbiao.gan@med.nyu.edu.cn; ZHANG Xue-Ji , zhangxueji@szu.edu.cn

Received Date: 2019-07-20

Fund Project: This work was supported by the National Natural Science Foundation of China (Nos. 21877081, 21890740, 21890742, 21727815), the Guangdong Natural Science Foundation for Major Cultivation Project (No. 2018B030336001) and the Shenzhen Science and Technology Foundation (No. JCYJ20180305124018343).

阿尔茨海默病（Alzheimer's disease，AD）是老年人中的主要痴呆类型。目前临床用药物只能缓解症状、无治疗效果，因此，亟需开发有效的AD治疗药物。本研究以三转基因AD模型小鼠3×Tg-AD为研究对象，对2月龄AD小鼠分别给予0.2和1.0 mmol/L乙基麦芽酚氧钒（BEOV）饮用水2个月，采用旷场实验、高架十字迷宫、Y迷宫3种行为学测试法，发现BEOV可以显著改善4月龄AD小鼠的自发活动、探索和记忆能力、减轻小鼠的焦虑状态。采用活体荧光成像技术在体追踪检测2.5和3.5月龄小鼠脑皮层神经元树突棘的变化，发现YFP荧光小鼠树突棘数量呈增多趋势；而3×Tg-AD与YFP小鼠杂交后代AD-YFP小鼠的树突棘则呈下降趋势。与AD-YFP鼠相比较，补充1.0 mmol/L BEOV的AD-YFP小鼠，脑皮层神经元总树突棘、蘑菇型树突棘、细小型树突棘数量均呈显著增加，说明BEOV可保护神经元、减少小鼠树突棘的丢失。采用电感耦合等离子体质谱（ICP-MS）检测3×Tg-AD鼠脑金属离子水平，结果表明，1.0 mmol/L BEOV能显著提高鼠脑V和Se的水平、降低Fe、Zn、Hg、Pb、Bi和Ni的水平，说明V可与Se协同调控AD鼠脑中多种金属离子水平。本研究表明，BEOV可通过调控AD鼠脑中多种金属离子的内稳态平衡，保护神经细胞，抑制AD小鼠神经元树突棘丢失，从而增强小鼠记忆能力，干预AD病理进程。

关键词: 阿尔茨海默病, 乙基麦芽酚氧钒, 活体荧光成像, 树突棘, 电感耦合-等离子体质谱

Alzheimer's disease (AD) is a major type of dementia in the elderly. Clinical medication at present can only relieve symptoms but has no therapeutical effect. Thus, it is urgent to develop an effective drug for the treatment of AD. In this study, 2-month-old triple transgenic AD model mice (3×Tg-AD) were treated respectively with 0.2 and 1.0 mmol/L bis(ethylmaltolato) oxidovanadium IV (BEOV) in drinking water for 2 months. The open field test, the elevated plus-maze test and the Y maze test were applied to those mice, showing that BEOV could significantly improve the exploratory ability, memory capacity and exercise ability and relieve the anxiety of 4-month-old 3×Tg-AD mice. The dendritic spines of pyramidal neurons in neocortex were detected by in-vivo two-photon imaging of YFP and AD-YFP mice (the offspring of 3×Tg-AD and YFP mice). The numbers of dendritic spines increased in YFP mice but decreased in AD-YFP mice from 2.5-month-old to 3.5-month-old. Treatment with 1.0 mmol/L BEOV in the AD-YFP mice significantly increased the numbers of total dendritic spines, mushroom spines and thin spines, which suggested that BEOV could protect cortical neurons and reduce the loss of dendritic spines. The levels of metal ions in the brain of mice were further measured by inductively coupled plasma mass spectrometry (ICP-MS). The results showed that 1.0 mmol/L BEOV could significantly increase the levels of V and Se and decrease the levels of Fe, Zn, Hg, Pb, Bi and Ni in AD brains, implying that vanadium might synergize with selenium to regulate the levels of metal ions in AD mice. Summarily, BEOV could mediate the homeostasis of multiple metal ions in AD brain and protect cortical neurons and thus to interfere with the pathological process of AD.

Key words: Alzheimer's disease, Bis(ethylmaltolato) oxidovanadium IV, In-vivo fluorescence imaging, Dendritic spines, Inductively coupled plasma mass spectrometry

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研究报告

活体荧光成像结合金属离子检测研究乙基麦芽酚氧钒对阿尔茨海默病的作用

何志军, 白杨, 赵琼晖, 欧阳霈, 倪嘉缵, 刘琼, 甘文标, 张学记

关键词: 阿尔茨海默病, 乙基麦芽酚氧钒, 活体荧光成像, 树突棘, 电感耦合-等离子体质谱

Application of in Vivo Fluorescence Imaging and Metal Ion Detection for Investigation of Bis (ethylmaltolato) Oxidovanadium(Ⅳ) on Alzheimer's Disease

HE Zhi-Jun , BAI Yang , ZHAO Qiong-Hui , OUYANG Pei , NI Jia-Zuan , LIU Qiong , GAN Wen-Biao , ZHANG Xue-Ji

Key words: Alzheimer's disease, Bis(ethylmaltolato) oxidovanadium IV, In-vivo fluorescence imaging, Dendritic spines, Inductively coupled plasma mass spectrometry

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