CN113750121A - 一种狄氏副拟杆菌在制备阿尔茨海默病药物制剂中的应用 - Google Patents
一种狄氏副拟杆菌在制备阿尔茨海默病药物制剂中的应用 Download PDFInfo
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Abstract
本发明涉及一种狄氏副拟杆菌在制备阿尔茨海默病药物制剂中的应用。本发明给予阿尔茨海默病模型APP/PS1小鼠灌胃狄氏副拟杆菌能够显著缓解模型小鼠的阿尔茨海默病的病理改变，因此，狄氏副拟杆菌可能成为益生菌的候选对象，用于阿尔茨海默病患者的治疗新途径和新方法。
Description
技术领域
本发明属于阿尔茨海默病领域，特别涉及一种狄氏副拟杆菌在制备阿尔茨海默病药物制剂中的应用。
背景技术
阿尔茨海默病(Alzheimer's disease,AD)是一种严重威胁人类健康及生活质量的神经退行性疾病，是老年人群中常见的引起痴呆的病因。在全球范围内，目前AD患者已有3000万例，并且随着世界人口老龄化，这一数字预计在2050年将上升至9000万(Prince etal.2015)。中国拥有世界最大的痴呆患者人群，给社会及家庭带来了巨大压力。AD病程通常有三个阶段：临床前期、轻度认知障碍(mild cognitive impairment，MCI)和痴呆。AD的病理表现主要为脑内广泛存在的由胞外β淀粉样蛋白(amyloid beta，Aβ)聚集形成的斑块和过度磷酸化的tau蛋白在胞内形成的神经原纤维缠结。AD的发病以散发病例居多，现有的许多研究表明，神经炎症、感染等也是AD发病的重要风险因素。迄今为止，脑内Aβ及tau蛋白的沉积仍然是AD病理诊断的金标准(Long et al.2019)。
目前共有四种经FDA批准的药物用于治疗AD患者的认知障碍。这包括三种胆碱酯酶抑制剂(多奈哌齐、卡巴拉汀、加兰他敏)和一种非竞争性NMDA受体调节剂(美金刚)(Livingston,et al.2017)。这两类药物均能够在AD的症状控制上起作用，但对于疾病的长期进展均无显著疗效。另外，有许多针对Aβ、Tau、ApoE等病理标志物以及聚焦于血液成分及免疫系统进行干预的药物研究。引起磷酸化的激酶可以被GSK-3抑制剂来抑制如Tideglusib，该抑制剂具有改善认知、减少神经退行性变及tau磷酸化的作用，这一作用已通过表达tau蛋白的转基因小鼠的临床研究得到证实(Cortés-Gómez et al.2021)。目前有超过20余种化合物已经完成了针对AD不同阶段患者的三期临床试验，但都没有显示出在减缓认知能力下降或改善整体功能方面的疗效(Long et al.2019；Kodamullil etal.2017)。Biogen公司最近针对其抗AD药物Aducanumab临床试验数据进行了深入分析，认为达到了预期治疗目标，但是引起了业界很大争议(Schneider.2020)。近期报道的甘露寡糖二酸(GV-971)的三期临床研究显示，可以改善AD患者的认知功能(Wang X et al.2019)。尽管如此，目前尚无药物具有疾病修饰的作用和能够明确延缓疾病的进展。因此，迫切需要开发能够改善AD临床症状同时阻止疾病病理进程的治疗策略和药物。
发明内容
本发明所要解决的技术问题是提供一种狄氏副拟杆菌在制备阿尔茨海默病药物制剂中的应用，为阿尔茨海默病患者的治疗新途径和新方法提供新的思路。
本发明提供了一种狄氏副拟杆菌在制备阿尔茨海默病药物制剂中的应用。
所述狄氏副拟杆菌呈活细菌、非复制性细菌形式。
所述狄氏副拟杆菌的量为109-1011cfu/ml。
所述药物制剂形式为悬液。
所述药物制剂给予方式为口服。
所述药物制剂用于食品、药物组合物、营养制剂、保健品、食品补充剂或食品添加剂。
前期研究采用肠道菌群16S RNA检测技术在早期AD患者的粪便中发现狄氏副拟杆菌较健康对照组存在明显减低，提示补充狄氏副拟杆菌可以纠正AD患者的肠道菌群失衡，从而改善AD患者的认知功能，这为开发一种能够改善AD临床症状的同时可以阻止疾病病理进程的治疗策略和药物，提供了新思路和新方法。
有益效果
阿尔茨海默病为大脑皮层与海马β淀粉样蛋白沉积等病理改变而导致临床产生认知功能障碍，本发明给予AD模型APP/PS1小鼠灌胃狄氏副拟杆菌能够显著缓解小鼠的阿尔茨海默病的病理改变，因此，狄氏副拟杆菌可能成为益生菌的候选对象，用于阿尔茨海默病患者的治疗新途径和新方法。
附图说明
图1A为野生型(WT)和APP/PS1年轻小鼠大脑切片中海马区(CA1,CA2/3,DG)和皮层(CTX)Aβ1-42的免疫荧光染色图像。
图1B为海马区Aβ1-42阳性面积占总视野面积比例分析。
图1C为皮层区Aβ1-42阳性面积占总视野面积比例分析。
图2A为野生型(WT)和APP/PS1年轻小鼠大脑切片中海马区LAMP1的免疫荧光染色图像。
图2B为LAMP1阳性面积占总视野面积比例分析。
图3A为野生型(WT)和APP/PS1年轻小鼠大脑切片中海马区COX2的免疫荧光染色图像。
图3B为COX2阳性面积占总视野面积比例分析。
图4为野生型(WT)和APP/PS1年轻小鼠血清中FITC标记的右旋糖酐含量分析。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
本实施例采取的是将狄氏副拟杆菌活菌悬液口服(灌胃)的给予方式，按照1x109cfu/ml的浓度，每只小鼠200ul/日，每日灌胃1次，持续30天。后续可进一步开发更方便安全的口服制剂。
针对AD模型APP/PS1小鼠(AD模型小鼠为Thy1-APPsw/PSL166P转基因小鼠(129S品系)，简称APP/PS1小鼠，来自上海交通大学医学院附属瑞金医院神经病学研究所，该小鼠引进自德国Rebecca Radde实验室。转基因小鼠造模：将Thy1-APPKM670/671NL和Thy1-PS1L166P共注射到C57BL6J卵母细胞雄性原核细胞中，随后产生的雄性小鼠进一步与C57BL/6J小鼠交配。(Radde et al.2006))，灌胃给予狄氏副拟杆菌，能够显著减少皮层与海马淀粉样斑块沉积(见图1)，减轻海马区神经元轴突变性(见图2)，减弱海马区炎症反应(见图3)。进一步运用荧光标记的右旋糖酐灌胃实验显示，给予狄氏副拟杆菌组的APP/PS1小鼠相较给予PBS的小鼠，其血液中荧光标记的右旋糖酐浓度明显下降(见图4)，表明喂食狄氏副拟杆菌具有维护肠道机械屏障完整、减少肠道异常通透的作用。
阿尔茨海默病为大脑皮层与海马β淀粉样蛋白沉积等病理改变而导致临床产生认知功能障碍，本发明给予AD模型APP/PS1小鼠灌胃狄氏副拟杆菌能够显著缓解小鼠的阿尔茨海默病的病理改变，因此，狄氏副拟杆菌可能成为益生菌的候选对象，用于阿尔茨海默病患者的治疗新途径和新方法。
Claims (6)
1.一种狄氏副拟杆菌在制备阿尔茨海默病药物制剂中的应用。
2.根据权利要求1所述的应用，其特征在于：所述狄氏副拟杆菌呈活细菌、非复制性细菌形式。
3.根据权利要求1所述的应用，其特征在于：所述狄氏副拟杆菌的量为109-1011cfu/ml。
4.根据权利要求1所述的应用，其特征在于：所述药物制剂形式为悬液。
5.根据权利要求1所述的应用，其特征在于：所述药物制剂给予方式为口服。
6.根据权利要求1所述的应用，其特征在于：所述药物制剂用于食品、药物组合物、营养制剂、保健品、食品补充剂或食品添加剂。
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