CN117427090A - miR-137-3p在制备阿尔茨海默病神经炎症药物的用途 - Google Patents
miR-137-3p在制备阿尔茨海默病神经炎症药物的用途 Download PDFInfo
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Abstract
本发明公开了miR‑137‑3p在制备阿尔茨海默病神经炎症药物的用途。通过在脑内补充miR‑137‑3p能够改善AD小鼠模型的神经炎症，减少神经元丢失并提高AD小鼠学习记忆能力。研究证明，miR‑137‑3p激活有效改善AD神经炎症，为AD抗炎治疗提供新思路。
Description
技术领域
本发明涉及生物医药领域；具体涉及miR-137-3p在制备阿尔茨海默病神经炎症药物的用途。
背景技术
阿尔茨海默病(Alzheimer's disease,AD)是一种以进行性认知功能障碍为特征的神经退行性疾病，是导致痴呆最主要的原因。如仍缺乏有效的防治方法，预计到2050年我国将有2000万患者罹患AD，因此，寻求有效的AD防治方法迫在眉睫。
microRNA(miRNA)是通过调节细胞内蛋白的表达来发挥其生物学功能的小分子RNA，调控约80％的人类基因，其表达失调会加速AD的发生发展。随着对miRNA疗法的深入了解，越来越多的证据表明，miRNA疗法可能是AD防治的重要突破。
miR-137-3p是神经发育调控的关键枢纽，在大脑中富集，参与卒中、精神分裂症等多种神经系统疾病的调控。miR-137在AD患者的脑组织中表达下调，但miR-137是否与AD神经炎症有关，目前暂未出现通过提高miR-137-3p表达量减轻AD神经炎症的报道。
发明内容
miR-137-3p在脑内富集，是神经发育的关键调控枢纽，研究发现miR-137-3p可减轻Aβ诱导的神经细胞死亡，但其是否参与调节AD神经炎症尚未见报道。
因此，本发明旨在提供miR-137-3p在制备用于改善AD神经炎症的试剂中的应用。
为实现上述目的，本发明采用如下技术方案：
本发明提供了miR-137-3p在制备阿尔茨海默病神经炎症药物的用途。
优选地，所述miR-137-3p核苷酸序列为：
UUAUUGCUUAAGAAUACGCGUAG。
本发明还提供了miR-137-3p过表达载体在制备阿尔茨海默病神经炎症药物的用途。具体的，所述的miR-137-3p过表达载体为外源基因为miR-137-3p的腺病毒过表达载体。所述的miR-137-3p核苷酸序列为：UUAUUGCUUAAGAAUACGCGUAG。
优选地，所述的腺病毒过表达载体为ITR-PCMV-bGlobin-EGFP-MCS-PolyA。
本发明还提供一种阿尔茨海默病神经炎症药物，其特征在于包括外源基因为miR-137-3p的腺病毒过表达载体。
优选地，所述的miR-137-3p核苷酸序列为：
UUAUUGCUUAAGAAUACGCGUAG；所述的腺病毒过表达载体为ITR-P CMV-bGlobin-EGFP-MCS-PolyA。
本方还提供了一种阿尔茨海默病神经炎症药物的筛选方法，包括以下步骤：
(1)将候选药物处理实验动物；
(2)检测实验动物体内miR-137-3p的表达水平；
(3)若miR-137-3p的表达水平升高；则候选药物为有效药物。
优选地，步骤(2)中的检测方法为荧光定量PCR。
本发明具有但不限于以下有益效果：
本发明实验证明所构建的miR-137-3p过表达腺相关病毒注射至AD小鼠双侧海马区，能明显减轻AD神经炎症，从而减少神经元丢失并提升AD小鼠学习记忆能力。本发明所设涉及的miR-137-3p在治疗AD神经炎症的产品中的应用，具有潜在应用价值。
与现有技术相比，本发明结果显示：脑内补充miR-137-3p能够改善AD小鼠模型的神经炎症，减少神经元丢失并提高AD小鼠学习记忆能力。研究证明，miR-137-3p激活有效改善AD神经炎症，为AD抗炎治疗提供新思路。
附图说明
为了清楚地展示本发明具体的实施方式以及在实验中采用的某些检测技术，下面将对实施方案及采用的技术进行描述，主要通过附图的形式进行介绍。
图1miR-137-3p腺相关病毒的构建。
图2miR-137-3p减轻AD小鼠的神经炎症。
图3miR-137-3p减轻AD小鼠的神经元丢失。
图4miR-137-3p改善AD小鼠的空间参考能力和短期记忆。
图5miR-137-3p改善AD小鼠的学习记忆能力。
图6 miR-137-3p改善AD小鼠的长期记忆能力。
具体实施的方式
本发明具体的实施方式通过实施例来辅助解释，除检测所用的技术对本发明不做任何形式的限制外，描述的实施例中部分方案属发明的一部分实施例，在本领域的普通技术操作人员在没有创造性的成果获得的实施例，均属本发明的保护范围。本部分对本发明试验中所使用到的材料以及试验方法进行一般性的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的，但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚，在上下文中，如果未特别说明，本发明所用材料和操作方法是本领域公知的。
实施例1
miR-137减轻AD小鼠的神经炎症
将所构建的miR-137-3p过表达腺相关病毒载体(图1)注射至AD小鼠双侧海马区，对小鼠脑组织进行实验检测(本实施例所获的脑组织同样用于实施例2-5的检测)，具体如下：
本发明使用Iba1抗体标记小胶质细胞，分析miR-137对AD小鼠小胶质细胞数量的影响。
具体过程包括：脑组织冰冻切片用脑片封闭液室温孵育2h。添加IBA1一抗(1：200)在37℃下孵育1h，然后在室温下将荧光偶联二抗(1：400)和DAPI(1：2000)孵育2h，PBS清洗后封片。在LSM800激光扫描共聚焦荧光显微镜拍摄图像。结果显示，miR-137显著减少APP/PS1小鼠海马区小胶质细胞数量(图2)。
实施例2
miR-137减轻AD小鼠的神经元丢失
Nissl染色是一种广泛用于研究神经组织形态和病理学的方法。本发明通过神经元胞体是否完整、尼氏小体颜色等评估神经元受损情况。
具体过程包括：(1)脱蜡：石蜡切片依次进行以下操作，二甲苯I 5min二甲苯II5min无水乙醇I 5min无水乙醇II 5min75％乙醇5minddH2O 2min。(2)染色：用0.22μm过滤器过滤尼氏染色液，37℃染色5min(避光)。(3)冲洗：ddH2O洗涤2次，每次30s。(4)透明：二甲苯透明5min。晾干，换用新鲜的二甲苯，再透明5min。(5)封片：中性树胶封片。(6)拍摄：显微镜下观察。大量研究表明，AD中的神经元大量丢失。本发明通过Nissl染色对比miR-137过表达干预后AD小鼠海马CA1区的神经元数量变化。结果显示，与APP/PS1+Vector组相比，miR-137干预组小鼠CA1区域的正常神经元数量明显增多(图3A-B)。简而言之，尼氏染色的结果证明miR-137有助于减轻APP/PS1小鼠的神经元丢失，为miR-137改善AD小鼠的认知功能提供形态学证据。
实施例3
miR-137改善AD小鼠的空间参考能力和短期记忆
Y迷宫测试可以帮助评估小鼠的空间参考能力和短期记忆。为了确定miR-137对AD小鼠模型短期工作记忆的治疗效果，本发明对小鼠进行Y迷宫测试，并记录小鼠进入Y迷宫手臂的序列以及次数，以分析小鼠的空间工作能力和短期记忆能力。
具体过程包括：小鼠将随机从不同的Y迷宫手臂放入，以排除左右偏好。当小鼠穿过Y迷宫中心的三角区域即为1次进/出手臂。小鼠依次进入不同的Y迷宫手臂记录为1次交替。交替次数/(总的进入手臂次数-2)×100即为自由交替百分比。在Y迷宫测试中，与WT组相比，APP/PS1小鼠自发交替次数呈显著下降趋势(图4)。miR-137过表达干预后，小鼠表现出比APP/PS1组更好的自由交替比例(图2)，提示miR-137过表达可在一定程度上改善小鼠的短期工作记忆。
实施例4
miR-137改善AD小鼠的学习记忆能力
为了明确miR-137对AD小鼠模型学习记忆的影响，本发明进行了新物体识别测试。
具体过程包括：测试分为3个阶段，分别是适应阶段、训练阶段和测试阶段，每个阶段之间间隔1h。适应阶段为了消除小鼠对环境的恐惧，减少小鼠因恐惧造成的实验误差。训练阶段小鼠可以自由探索两个相同的物体，1h后将其中一个物体更换为大小、体积相似，颜色、形状差异明显的新物体。通过识别指数(Recognition Index,RI)、歧视指数(Discrimination Index,DI)将测试阶段的具体数据量化。探索新物体的时间/探索新旧物体花费的总时间×100可以得到识别指数RI。图5的结果显示看到WT+Vector组、WT+miR-137组探索新物体的时间无明显差异(图5)，APP/PS1组小鼠探索新物体所花费的时间相较WT组及WT+miR-137组明显减少(图5)，miR-137过表达干预可以增加APP/PS1小鼠探索新物体的时间(图5)。NOR的结果表明miR-137过表达在一定程度上可以帮助维持APP/PS1小鼠的学习记忆能力。
实施例5
miR-137帮助维持AD小鼠的空间参考和长期记忆能力
为了明确miR-137对APP/PS1模型小鼠空间学习和长期记忆能力的影响，本发明进行了水迷宫(MWM)测试。
具体过程包括：将小鼠面向水池边缘，尾部朝下轻放入。小鼠在1min自由寻找水下的隐藏平台，如果小鼠在1min内没有找到平台，则将其引导到平台位置，并停留20s，然后放回原笼；如小鼠1min内找到平台，也放置在平台上20s后放回原笼。每天进行3次训练。训练7日，训练结束24h后测试，此阶段会将平台从池中撤出后，将小鼠从平台象限距离最远的点放入，自由探索1min，由软件记录并分析。结果表明，与对照组(WT+Vector、WT+miR-137)相比，AD小鼠(APP/PS1)表现出逃逸潜伏期更长(图6A)，穿越隐藏平台次数更少(图6B)，而miR-137过表达改善了APP/PS1小鼠的上述指标，增强了APP/PS1小鼠的空间学习和长期记忆能力。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，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。
Claims (10)
1.miR-137-3p在制备阿尔茨海默病神经炎症药物的用途。
2.如权利要求1所述的用途，其特征在于：所述miR-137-3p核苷酸序列为：UUAUUGCUUAAGAAUACGCGUAG。
3.miR-137-3p过表达载体在制备阿尔茨海默病神经炎症药物的用途。
4.如权利要求3所述的用途，其特征在于：所述的miR-137-3p过表达载体为外源基因为miR-137-3p的腺病毒过表达载体。
5.如权利要求3所述的用途，其特征在于：所述的miR-137-3p的核苷酸序列为：UUAUUGCUUAAGAAUACGCGUAG。
6.如权利要求3所述的用途，其特征在于：所述的腺病毒过表达载体为ITR-P CMV-bGlobin-EGFP-MCS-PolyA。
7.一种阿尔茨海默病神经炎症药物，其特征在于：所述药物为外源基因为miR-137-3p的腺病毒过表达载体。
8.如权利要求7所述的药物，其特征在于：所述的miR-137-3p核苷酸序列为：UUAUUGCUUAAGAAUACGCGUAG；所述的腺病毒过表达载体为ITR-P CMV-bGlobin-EGFP-MCS-PolyA。
9.一种阿尔茨海默病神经炎症药物的筛选方法，其特征在于包括以下步骤：(1)将候选药物处理实验动物；
(2)检测实验动物体内miR-137-3p的表达水平；
(3)若miR-137-3p的表达水平升高；则候选药物为有效药物。
10.如权利要求9所述的筛选方法，其特征在于：步骤(2)中的检测方法为荧光定量PCR。
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| CN104011210A (zh) * | 2011-10-11 | 2014-08-27 | 布里格姆及妇女医院股份有限公司 | 神经退行性病症中的microRNA |
Non-Patent Citations (2)
| Title |
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| HE D ET AL: "miR-137 attenuates Aβ-induced neurotoxicity through inactivation of NF-κB pathway by targeting TNFAIP1 in Neuro2a cells", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 490, 24 June 2017 (2017-06-24), pages 942 * |
| 姜扬 等: "miR-137参与阿尔茨海默病分子机制的研究进展", 山东医药, vol. 57, no. 36, 31 December 2017 (2017-12-31), pages 100 - 102 * |
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