Development of a Zebrafish Model for Rapid Drug Screening against Alzheimer＇s Disease
Development of a Zebrafish Model for Rapid Drug Screening against Alzheimer＇s Disease
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DOI：
10.17265/2328-2150/2016.04.003
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发表时间：
2016-04
影响因子：
3.3
通讯作者：
Wen-hai;Huang;Chuansheng;Li;Zhengrong;Shen;Xiaoyu;Zhu;Bo;Xia;Chunqi
中科院分区：
文献类型：
--
作者：
Wen-hai;Huang;Chuansheng;Li;Zhengrong;Shen;Xiaoyu;Zhu;Bo;Xia;Chunqi
阿尔茨海默病是导致老年人痴呆的主要原因，是一种复杂的神经退行性疾病，会导致认知功能的进行性下降。为了从大量的化合物中鉴定和评价抗阿尔茨海默病的新药，迫切需要一种快速筛选模型。到目前为止，许多研究都是利用斑马鱼模型进行药物发现。由于铝可以诱导斑马鱼与阿尔茨海默病患者相似的生物学活性，在本研究中，我们通过优化铝暴露的剂量和时间，建立了一种新的动物模型，使用受精后3-5天的斑马鱼幼体。为了验证新开发的斑马鱼模型，对六种具有各种机制的抗阿尔茨海默病药物进行了测试。重要的是，利凡斯明、THT、氟比洛芬和AM-117可使运动障碍恢复率分别提高53.4-%、169.4-200%、54.5-96%和70.9-121%。利凡斯明、美金刚、THT、氟比洛芬、罗格列酮和AM-117的有效率分别提高86.6~175.1%、28.2~66.6%、127.2~236.5%、118.3~323.7%、26.6~140.8%和70.2~161.4%。我们的结果表明，本研究建立的斑马鱼模型可以作为高通量筛选针对乙酰胆碱酯酶、N-甲基-D-天冬氨酸受体、γ分泌酶、过氧化物酶体增殖物激活受体-γ和淀粉样蛋白-β的潜在抗阿尔茨海默病先导化合物的有用工具。
Alzheimer’s disease, the leading cause of dementia in the elderly, is a complex neurodegenerative disorder which leads to a progressive decline in cognitive functions. A rapid screening model is highly demanded for identification and evaluation of novel anti-Alzheimer’s disease drugs from a large numbers of compounds. Until now, numerous studies utilized zebrafish model for drug discovery. Since aluminum can induce a similar biological activity in zebrafish as in Alzheimer patients, in this study, we developed a novel animal model using 3 to 5 day post-fertilization larval zebrafish by optimizing the doses and duration of aluminum chloride exposure. Six anti-Alzheimer’s disease drugs with a variety of mechanisms were tested to validate the newly developed zebrafish model. Importantly, Rivastigmine, ThT, Flurbiprofen and AM-117 could increase the value of Dyskinesia Recovery Rate by 53.4-64%, 169.4-200%, 54.5-96% and 70.9-121%, respectively. Rivastigmine, Memantine, ThT, Flurbiprofen, Rosiglitazone and AM-117 improved the value of Response Efficiency by 86.6-175.1%, 28.2-66.6%, 127.2-236.5%, 118.3-323.7%, 26.6-140.8% and 70.2-161.4%, respectively. Our results suggest that the zebrafish model developed in this study could be a useful tool for high throughput screening of potential novel anti-Alzheimer’s disease leading compounds targeting acetylcholinesterase, N-methyl-D-aspartic acid receptor, γ-secretase, peroxisome proliferator-activated receptor-γ and amyloid-β.