抑制IDO过度活化对阿尔茨海默病小鼠认知缺陷的改善及其机制研究

Indoleamine 2,3-dioxygenase (IDO) and it catabolizing kynurenine pathway (KP) of tryptophan metabolism have been implicated in the pathogenesis of Alzheimer's disease (AD). Inhibition of IDO has emerged as a new strategy in AD therapy. However, most known IDO inhibitors bear poor efficiency and low blood-brain barrier (BBB) permeability. Therefore,the application of IDO inhibitor in AD treatment has been obstructed. In the previous studies, we found that coptisine and 2-fluorotryptanthrin were potent IDO inhibitors with good BBB permeability, observeded the over-expression of IDO and upregulagted KP in the APP/PS1 transgenic AD mouse, and demonstrated that coptisine remarkably suppressed the upregulated KP and ameliorated the impaired cognition in AD mouse. In the present study, we will evaluate the effects of IDO inhibitors on cognitive and neurological impairment in AD mouse, and explore the potential mechanism. The Morris water maze assay for the spatial learning performance and immunohistochemistry analysis for amyloid plaque, synaptic and neuronal cell will be performed. For the mechanism study, the effects of the IDO inhibitors on the expression and activity of IDO, the regulation of KP, the activation of microglia and astrocytes both in vivo and in vitro, and neuron protection in vitro will be explored. This study will elucidate the therapeutic effect and the potential mechanism of IDO inhibitors on AD, and offer new potent scientific basis for AD therapy and anti AD drug development.

吲哚胺2,3-双加氧酶（IDO）是催化色氨酸沿犬尿氨酸途径（KP）代谢的限速酶。IDO的过度活化及KP的失调与阿尔茨海默病（AD）的发病机理有关，抑制IDO过度活化是AD治疗的新策略。由于缺乏理想的IDO抑制剂，有关IDO抑制剂抗AD作用的研究尚未见报道。前期工作中我们筛选到可透过血脑屏障的高效IDO抑制剂黄连碱和2-氟色胺酮；确认APP/PS1转基因AD小鼠脑中IDO的高表达、体内KP的上调；证实黄连碱可以遏制AD小鼠体内KP的上调、改善其认知功能。本项目拟在此基础上，进一步验证IDO抑制剂对AD小鼠的治疗作用：行为学实验评价其对AD小鼠认知能力的影响，免疫组化分析其对AD小鼠脑内病理特征的影响；并开展作用机制研究：整体和离体水平分析其对KP上调及神经胶质细胞活化的调控；离体水平研究其对神经元的保护。本项目将阐明IDO抑制剂对AD的治疗学效果及其机制，为AD治疗和药物研究提供新思路。

吲哚胺2,3-双加氧酶（IDO）是催化色氨酸沿犬尿氨酸途径（KP）代谢的限速酶。IDO的过度活化及KP的失调与阿尔茨海默病（AD）的发病机理有关，抑制IDO过度活化是AD治疗的新策略。由于缺乏理想的IDO抑制剂，有关IDO抑制剂抗AD作用的研究尚未见报道。前期工作中我们筛选到可透过血脑屏障的高效IDO抑制剂黄连碱和2-氟色胺酮；确认APP/PS1转基因AD小鼠脑中IDO的高表达、体内KP的上调。本项目在此基础上，研究IDO抑制剂对AD小鼠的治疗作用：行为学实验评价其对AD小鼠认知能力的影响，免疫组化分析其对AD小鼠脑内病理特征的影响；并开展作用机制研究：整体和离体水平分析其对KP上调及神经胶质细胞活化的调控；离体水平研究其对神经元的保护。本项目按计划进行，在计划时间内完成了各项研究内容，解决了三个关键问题⑴ 获得可用于动物水平AD 治疗学研究的IDO 抑制剂；⑵ 从动物水平揭示IDO 抑制剂治疗AD 的作用；⑶ 在细胞、分子水平阐明IDO 抑制剂对KP 及神经细胞的调控。本项目超额完成预定的成果指标，发表SCI论文7篇，其中二区论文6篇；发表中文核心期刊论文7篇；申请中国发明专利4项，其中2项授权；申请世界发明专利1项；先后获得中国药学会科学技术奖（省部级，2017年，三等，排名第一），上海市药学科技奖（2016年，一等，排名第一）；培养博士生1名，硕士研究生9名。本项目阐明了IDO抑制剂对AD的治疗学效果及其机制，为AD治疗和药物研究提供新思路。