CN115463215A - Hdac9及其抑制剂的新用途 - Google Patents
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Abstract
本发明属于生物技术领域，尤其涉及HDAC9及其抑制剂的新用途，具体公开了去乙酰化酶HDAC9在治疗记忆力障碍中作为抑制靶点的应用。去乙酰化酶HDAC9的活性抑制剂在制备记忆力障碍疾病药物中的应用。CaM乙酰化水平检测试剂或HDAC9表达水平检测剂在制备阿尔茨海默病检测产品中的应用。本发明主要针对记忆力障碍(尤其是AD记忆障碍)的病理机制，有效增加AD大脑神经元钙调蛋白(Calmodulin,CaM)乙酰化及CaMKIIα/GluR1磷酸化水平，增强相关学习记忆，进而缓解AD记忆障碍。
Description
技术领域
本发明属于生物技术领域，尤其涉及HDAC9及其抑制剂的新用途。
背景技术
目前CaM乙酰化调节制剂以及HDAC9的非组蛋白去乙酰化底物还有很大 的研究空间。CaM乙酰化调节制剂也包括医药用途和非医药用途，医药用途的 调剂制剂主要用于治疗CaM相关的疾病，非医药用途的则可作为体外的调节制 剂，常见的如生物制剂等。虽然现有一些研究提供了一些新的可以对CaM促乙 酰化或去乙酰化的产品，但仍有所欠缺，还需要研究完善。
CaM乙酰化障碍等也都可能会引起记忆力障碍。记忆力障碍临床上表现为 记忆障碍、失语、失用、失认、空间能力损害、抽象思维损害、人格和行为改 变等，其具有多种不同的病症，包括记忆力障碍疾病包括空间记忆障碍、新物 体识别障碍和场景记忆障碍。
记忆障碍可能会形成阿尔茨海默病，而阿尔茨海默病也是造成记忆碍的原 因。目前对于记忆障碍和阿尔兹海默病病因研究尤为重要，患者的记忆功能减 退，主要是老年人的表现最为突出。比如记忆减退、抑郁症或者是情感障碍都 是大部分患者会有的，因此，病症要看不同年龄段患者的情况。
阿尔茨海默病(Alzheimer's disease,AD)是发生于老年或老年前期、以进行性认知和行为障碍为特征的中枢神经系统退行性病变。在过去几十年中，AD临床 试验大都失败，AD新药研发进展缓慢，目前治疗AD记忆障碍的药物屈指可数。 盐酸美金刚是非竞争性NMDA受体拮抗剂，可以适当改善AD认知障碍；胆碱 酯酶抑制剂(多奈哌齐、卡巴拉汀、加兰他敏、石杉碱甲)可以适当改善AD 认知障碍；阿杜那单抗(aducanumab)通过清除Aβ沉淀用于治疗AD；国内首个AD药物甘露特纳(GV-971)通过改善肠道菌群治疗AD。目前AD记忆障碍的具 体发病机制复杂多样，临床上缺乏有效的治疗手段。目前市面AD药物存在疗 效欠佳和副作用大等缺点。阿杜那单抗(aducanumab)十分昂贵，普及率低，有脑 水肿副作用。甘露特纳GV-971疗效甚微，改善肠道菌群治疗AD，机制不明。
针对记忆力障碍的研究还有所欠缺，一些治疗手段也有待完善。同时CaM 的体外乙酰化试剂也需要进一步研究完善。
发明内容
为了解决上述问题，本发明采用如下技术方案：
去乙酰化酶HDAC9在治疗记忆力障碍中作为抑制靶点的应用。
去乙酰化酶HDAC9的活性抑制剂在制备记忆力障碍疾病药物中的应用。
在一些方式中，所述记忆力障碍疾病包括空间记忆障碍、新物体识别障碍 和场景记忆障碍。
在一些方式中，所述记忆力障碍疾病包括AD记忆力障碍。
在一些方式中，去乙酰化酶HDAC9活性抑制剂的作用表现为
A.促CaM乙酰化，
B.促CaM下游CaMKIIα磷酸化，
C.促CaMKIIα下游GluR1磷酸化。
在一些方式中，所述去乙酰化酶HDAC9的活性抑制剂包括TMP269。
CaM乙酰化水平检测试剂或HDAC9活性水平检测剂在制备阿尔茨海默病 检测产品中的应用。
在一些方式中，所述阿尔茨海默病为AD记忆力障碍。
HDAC9活性抑制剂在制备治疗CaM蛋白去乙酰诱发病症中的应用。
HDAC9在制备体外CaM蛋白去乙酰化制剂非诊断治疗的应用。
在一些方式中，所述CaM蛋白为His-Ac-3K-CaM。
本发明的有益效果是：
本发明主要针对记忆力障碍(尤其是AD记忆障碍)的病理机制，有效增 加AD大脑神经元钙调蛋白(Calmodulin,CaM)乙酰化及CaMKIIα/GluR1磷酸化 水平，增强相关学习记忆，进而缓解AD记忆障碍。
附图说明
图1为钙调蛋白乙酰化异常降低参与阿尔茨海默病的病理机制；
图2为APP/PS1转基因小鼠血浆CaM乙酰化程度结果图；
图3为AD小鼠前脑CaM乙酰化程度结果图；
图4为HDAC9在HEK293细胞里去乙酰化CaM结果图；
图5为HDAC9体外直接去乙酰化CaM结果图；
图6为HDAC9抑制剂增加AD小鼠CaM乙酰化及CaMKIIα/GluR1磷酸化 结果图；
图7为HDAC9抑制剂改善海马依赖的空间记忆和新物体识别能力结果图；
图8为HDAC9抑制剂改善海马依赖的场景记忆能力结果图。
具体实施方式
下面对本发明做进一步说明：
本部分第一方面介绍：
去乙酰化酶HDAC9在治疗记忆力障碍中作为抑制靶点的应用，通过抑制 HDAC9的活性可实现缓解记忆力障碍。
去乙酰化酶HDAC9的活性抑制剂在制备记忆力障碍疾病药物中的应用。
其中之一，所述记忆力障碍疾病包括空间记忆障碍、新物体识别障碍和场 景记忆障碍，空间记忆障碍、新物体识别障碍和场景记忆障碍是常见的记忆力 障碍，空间记忆障碍和场景记忆障碍表现为对空间方位和场景环境的信息存在 功能异常。痴呆、脑外伤、应激所致记忆障碍、柯萨科夫综合征症状群均可能 出现记忆障碍。
其中之二，所述记忆力障碍疾病包括AD记忆力障碍，其主要为痴呆所致 的症状。
乙酰化酶HDAC9表达抑制剂的作用表现为
A.促CaM乙酰化，
B.促CaM下游CaMKIIα磷酸化，
C.促CaMKIIα下游GluR1磷酸化。
由此，HDAC9对由于CaM乙酰化异常降低、CaM下游CaMKIIα磷酸化异 常降低、CaMKIIα下游GluR1磷酸化异常降低导致的记忆力障碍均有治疗作用。 其中的促进包括提升水平、促其维持正常水平。
在一些方式中，所述去乙酰化酶HDAC9的活性抑制剂包括TMP269。
本部分第二方面介绍：
CaM乙酰化水平检测试剂或HDAC9表达水平检测剂在制备阿尔茨海默病 检测产品中的应用。当HDAC9表达水平增高时，CaM乙酰化水平降低，并且 两者呈负相关，由此还可通过检测HDAC9表达水平或CaM乙酰化水平实现对 阿尔茨海默病的检测。
其中，所述阿尔茨海默病为AD记忆力障碍。当HDAC9表达水平过高时， CaM乙酰化水平下降，都表征AD记忆力障碍。
本部分第三方面介绍：
HDAC9在制备体外CaM蛋白乙酰化制剂非诊断治疗的应用。现有的产品 基本都需要在体内实现CaM蛋白乙酰化进行调节，而本发明提出可直接通过HDAC9在体外就可实现去乙酰化CaM。
在一些方式中，所述CaM蛋白为His-Ac-3K-CaM、 His-Ac-K22/K95/K116-CaM中任一。
HDAC9活性抑制剂在制备治疗CaM蛋白乙酰化异常诱发病症中的应用。 CaM蛋白乙酰化异常诱发病症包括现有的已经证实的相关病症，具体可参考现 有技术资料。
本部分第四方面结合具体的研究项目做进一步说明：
AD遗传模型APP/PS1小鼠相对于野生型WT小鼠，血浆和大脑CaM乙酰 化水平显著降低，并且首次鉴定出CaM的去乙酰化酶HDAC9，以及抑制HDAC9 活性可以挽救AD小鼠大脑降低的CaM乙酰化及CaMKIIα/GluR1磷酸化和受损 的学习记忆。基于APP/PS1转基因AD小鼠实验结果，钙调蛋白乙酰化异常降 低参与阿尔茨海默病的病理机制：AD小鼠大脑CaM乙酰化异常降低损害 CaMKIIα/GluR1磷酸化信号转导通路，导致大脑学习记忆障碍，最终引起阿尔 茨海默病的病理进展(请见图1)。
一、AD小鼠血浆和大脑CaM乙酰化异常降低
检测7月龄WT和APP/PS1转基因小鼠(AD小鼠遗传模型)血浆中的CaM 乙酰化水平，方法如下，用泛乙酰化抗体(Ac-K antibody)通过免疫沉淀富集血浆 里总的乙酰化蛋白，再用CaM单抗检测总的乙酰化蛋白里乙酰化CaM(Ac-CaM) 的含量。
结果发现APP/PS1小鼠相对于WT小鼠，血浆CaM乙酰化水平显著降低(图 2中A和B)，且血浆CaM乙酰化降低在5月龄APP/PS1小鼠已经发生(图2 中C和D)，此时AD模型小鼠还未出现记忆障碍表型，而3月龄小鼠血浆CaM 乙酰化水平未发生明显改变(图2中E和F)。这些结果提示血浆CaM乙酰化异 常降低可能是阿尔茨海默病一种潜在的血浆早期诊断标志物。
图2：APP/PS1转基因小鼠血浆CaM乙酰化明显降低。A、C、E，分别是 7月龄、5月龄、3月龄WT和APP/PS1转基因小鼠血浆中CaM乙酰化水平的 western blot条带。B、D、F，分别是A、C、E图中Ac-CaM/CaM的定量分析， 以对照组为1进行标准化。*,p<0.05；**,p<0.01；t-test；n＝3。数据表示为平均值 ±标准误。
检测7月龄WT和APP/PS1小鼠前脑组织的CaM/CaMKIIα/GluR1信号转导 激活水平(图3中A)，结果发现APP/PS1小鼠相对于WT小鼠，前脑组织CaM 乙酰化显著降低(图3中B)，CaM下游CaMKIIα磷酸化及CaMKIIα下游GluR1 磷酸化显著降低(图3中C和D)，而CaM、CaMKIIα、GluR1、PSD95和CaM 乙酰转移酶SRC3总蛋白相对不变(图3中E、F、G、H和I)。这些结果提示大脑CaM乙酰化异常降低通过损害CaMKIIα/GluR1信号转导通路促进了阿尔茨 海默病的病理发展过程。
图3：AD小鼠前脑CaM乙酰化降低。A，对照和实验组前脑组织蛋白western blot条带。B、C和D，分别是Ac-CaM/CaM、p-CaMKIIα/CaMKIIα、p-GluR1/GluR1 的定量分析。E、F和G，分别是CaM、CaMKIIα、GluR1/α-tubulin的定量分析。 H和I，分别是PSD95和SRC3/α-tubulin的定量分析。以对照为1进行标准化。 ns,not significant；*,p<0.05；**,p<0.01；***,p<0.001；t-test；n＝4。数据表示为平 均值±标准误。
二、筛选并鉴定CaM的去乙酰化酶HDAC9
对HEK293细胞中几种存在于胞浆的HDAC进行了shRNA干扰。作为阳性 对照，用HDAC抑制剂TSA处理显著增加了Ac-CaM(图4中A和B)。HDAC shRNA的敲低效率得到蛋白质印迹验证(图4中A，C-G)。HDAC6 shRNA显 着增加α-tubulin乙酰化水平(图4中A和H)，这与之前的报告一致，作为另一 个阳性对照。HDAC9和HDAC6 shRNA均增加CaM乙酰化，其中HDAC9是 CaM最主要的去乙酰化酶，而HDAC4、HDAC7、HDAC8 shRNA则未明显表 现出增加CaM乙酰化(图4中A和B)。作为阴性对照，HDAC9 shRNA没有 增加α-tubulin乙酰化(图4中A和H)，表明HDAC9去乙酰化CaM的特异性。
图4：HDAC9是CaM主要的去乙酰化酶。A，在不同处理或shRNA转染 下HEK293细胞裂解液，分别用相应的抗体进行探测。TSA，HDAC抑制剂， 用作阳性对照。HDAC6 shRNA增加α-tubulin乙酰化是另一个阳性对照。B-H， 分别是各组Ac-CaM/CaM、HDAC4/α-tubulin、HDAC6/α-tubulin、 HDAC7/α-tubulin、HDAC8/α-tubulin、HDAC9/α-tubulin和Ac-tubulin/α-tubulin 的统计图。数据以对照组为1标准化。**,p<0.01；***p<0.001；one-way ANOVA；n＝3。数据表示为平均值±标准误。
CaM有三个赖氨酸位点(K22、K95和K116)可以发生乙酰化，并且在物 种间极其保守(图5中A)。为了验证HDAC9能否在体外直接去乙酰化CaM， 使用遗传密码子扩展方法纯化了定点乙酰化重组CaM蛋白(图5中B)。该方法 使用对乙酰化赖氨酸特异的工程化吡咯赖氨酰pyrrolysyl-tRNA合成酶及其同源 tRNAPry将Ac-K掺入指定的密码子，以产生位点特异性乙酰化蛋白。为了确定 CaM中三个赖氨酸位点中的哪一个被乙酰化，在K22、K95和K116位点制备 了针对CaM乙酰化的位点特异性抗体。如图5中C所示，通过泛乙酰化抗体和 位点特异性抗体检测，成功合成出三个位点乙酰化的Ac-3K-CaM以及Ac-K22、 K95和K116-CaM。接下来，将表达纯化的位点特异性乙酰化His-Ac-3K-CaM 和His-Ac-K22/K95/K116-CaM与从HEK293细胞中通过Flag磁珠纯化的带有 Flag标记的HDAC9一起孵育，结果表明HDAC9可以体外直接去乙酰化CaM 的K22、K95和K116位三个乙酰化位点。这是首次发现并鉴定出CaM的去乙 酰化酶HDAC9，同时CaM也是目前发现的HDAC9第一个非组蛋白去乙酰化 底物，也同时弥补了HDAC9的非组蛋白的去乙酰化底物的研究空白。
图5：HDAC9体外直接去乙酰化CaM。A，顶部，显示了小鼠CaM中乙 酰赖氨酸的位置，EF,EF hands，数字代表氨基酸。底部，来自不同物种的CaM 的氨基酸序列比对。红色的K表示可以发生乙酰化的赖氨酸。B，顶部，在大 肠杆菌中表达带His标签的乙酰化CaM重组蛋白的pCDF构建载体示意图。 底部，合成位点特异性乙酰化重组CaM蛋白的遗传密码子扩展方法原理图。C， 在大肠杆菌中表达带有His标签的乙酰化CaM蛋白(His-Ac-3K-CaM和 His-Ac-K22/K95/K116-CaM)的western blot条带，HDAC9可以体外直接去乙酰 化CaM的K22、K95和K116位三个乙酰化位点。
三、抑制HDAC9治疗AD记忆障碍的作用机制
阿尔茨海默病模型小鼠CaM乙酰化降低由其去乙酰化酶HDAC9表达升高 引起。HDAC9分别在5-7月龄和12月龄APP/PS1小鼠大脑中异常升高和降低 (图6中A和B)。往APP/PS1转基因AD小鼠侧脑室注射HDAC9抑制剂 TMP269，如图6中C-D所示，莫里斯水迷宫(Morris water maze,MWM)学习训 练可以增强AD小鼠前脑组织CaM乙酰化水平，而侧脑室注射HDAC9抑制剂 组(HDAC9 inhibitor,HDAC9 i)与Vehicle组比，HDAC9 i可以进一步增强小 鼠前脑组织CaM乙酰化水平，结果表明HDAC9可以在AD小鼠前脑内在体去 乙酰化CaM。之前研究表明CaM乙酰化可以增强CaMKIIα激活，使用针对 CaMKIIαThr286位点磷酸化特异性抗体检测CaMKIIα磷酸化，其磷酸化是 CaMKIIα激活的指标，如图6中C和E所示，CaMKIIα磷酸化升高与CaM乙 酰化增强保持一致。CaMKIIα可以磷酸化AMPA受体亚基GluR1 Ser831位点。 与CaMKIIα磷酸化升高一致，p-GluR1 Ser831在HDAC9 i组AD小鼠MWM学 习训练期间也得到进一步增加(图6中C和F)。这些结果表明，抑制HDAC9 可以改善AD小鼠参与水迷宫学习刺激激活的CaM乙酰化及CaMKIIα/GluR1 磷酸化信号级联反应。
图6：HDAC9抑制剂增加AD小鼠CaM乙酰化及CaMKIIα/GluR1磷酸化。 A，代表性印迹条带，APP/PS1小鼠前脑中的动态表达HDAC9蛋白水平。B， HDAC9/α-tubulin的统计图。C，水迷宫MWM训练可以增加APP/PS1转基因 AD小鼠前脑Ac-CaM、p-CaMKIIα、p-GluR1水平，而侧脑室注射HDAC9抑制 剂(HDAC9 i)与Vehicle组比，HDAC9 i可以进一步增强小鼠前脑Ac-CaM、 p-CaMKIIα、p-GluR1水平。D-F，分别是Ac-CaM/CaM、p-CaMKIIα/CaMKIIα、 p-GluR1/GluR1的定量分析。数据以对照为1标准化。**,p<0.01；***,p<0.001； one-way ANOVA；n＝4。数据表示为平均值±标准误。
四、抑制HDAC9治疗AD记忆障碍的作用效果
HDAC9抑制剂可以改善APP/PS1转基因AD小鼠海马依赖的学习记忆能 力。以莫里斯水迷宫(Morris water maze,MWM)行为范式研究海马依赖的空间 记忆，水迷宫是检测AD动物模型记忆障碍的金指标。在MWM训练期间，侧 脑室注射HDAC9抑制剂组(HDAC9 i)与Vehicle组比，HDAC9 i组AD小鼠 的学习曲线增强(图7中A)。在平台测试期间，与Vehicle组比，HDAC9 i组 AD小鼠停留在目标象限的时间和平台穿梭次数增加(图7中B-D)，Vehicle和HDAC9 i组AD小鼠的游泳速度相似(图7中E)。这些结果表明HDAC9抑制 剂可以改善AD小鼠海马依赖的空间学习记忆能力。接着，研究了HDAC9抑制 剂是否可以改善AD小鼠新物体识别(new object recognition,NOR)能力，新物体 识别是一种海马依赖的短期记忆行为范式，是检测AD动物模型记忆障碍的金 指标。与Vehicle组AD小鼠相比，HDAC9 i组AD小鼠辨别指数显著增强，Vehicle 和HDAC9 i组AD小鼠围绕新的和熟悉的物体的总探索时间相似(图7中F-G)。 这些结果表明HDAC9抑制剂可以改善AD小鼠海马依赖的短期记忆。以上结果表明抑制HDAC9可以改善AD小鼠海马依赖的学习记忆能力。
图7：HDAC9抑制剂改善海马依赖的学习记忆能力。A，在MWM训练期 间，侧脑室注射HDAC9抑制剂组(HDAC9 i)与Vehicle组比，HDAC9 i组 AD小鼠的学习曲线增强。*GenotypeF(1,170)＝8.842，p＝0.0041，two-way ANOVA，n＝15。数据表示为平均值±标准误。B，Vehicle组和HDAC9 i组AD 小鼠在平台测试期间的游泳轨迹。C，与Vehicle组AD小鼠相比，HDAC9 i组 AD小鼠停留在目标象限的时间增加。*,p＝0.0216，two-way ANOVA，n＝15。 数据表示为平均值±标准误。D，与Vehicle组AD小鼠相比，HDAC9 i组AD小 鼠平台测试期间穿过平台次数增加。E，Vehicle组和HDAC9 i组AD小鼠的游 泳速度相似。F，侧脑室注射Vehicle组和HDAC9 i组AD小鼠在新的(N)和熟 悉的(F)物体周围的头部热图。G，Vehicle组和HDAC9 i组AD小鼠之间用N 和F的相似总探索时间。H，识别指数统计表明HDAC9 i组AD小鼠新物体识 别受损。ns,not significant；*,p<0.05；***,p<0.001；t-test；n＝15。数据表示为平 均值±标准误。
最后，研究了HDAC9抑制是否可以挽救APP/PS1小鼠在场景恐惧记忆 中的记忆缺陷，场景恐惧记忆是海马依赖的场景记忆行为范式，是检测AD动 物模型记忆障碍的金指标。对小鼠进行场景条件性恐惧记忆训练(CS, conditioned stimulus，采用特定背景的箱子；US,unconditioned stimulus，采用 0.5mA足底电击)，一天后，当小鼠返回电击箱子时测试冻结时间(恐惧记忆) (图8中A)。侧脑室内注射溶剂或HDAC9抑制剂TMP269治疗的7月龄WT 和APP/PS1小鼠接受场景恐惧训练和测试流程图(图8中B)。在WT或APP/PS1 小鼠中，探索期间和刚训练后的冻结时间是相似的(图8中C)。而在一天后测 试期间注射TMP269的WT或APP/PS1小鼠增加了冻结时间(恐惧记忆)(图8 中C)，表明HDAC9抑制挽救了APP/PS1小鼠的场景恐惧记忆。另一方面， HDAC9抑制增强了WT小鼠的场景恐惧记忆(图8中C)。总之，这些结果表明 HDAC9抑制改善了APP/PS1小鼠的海马依赖的记忆缺陷。
图8：HDAC9抑制改善7月龄AD小鼠的情境恐惧记忆。A，场景恐惧条 件反射测试示意图。CS,conditioned stimulus，采用特定背景的箱子；US, unconditioned stimulus，采用0.5mA足底电击。B，行为学分组和测试的示意图。 C，侧脑室注射HDAC9抑制剂在配对测试期间分别增强或挽救WT或APP/PS1 小鼠的冻结时间(恐惧记忆)。**p<0.01,two-way ANOVAfollowed by Sidak’s multiple comparisons test,每组12小鼠，数据表示为平均值±标准误。
HDAC9介导的CaM去乙酰化在阿尔茨海默病中的病理机制，为治疗阿尔 茨海默病提供新的分子靶点。本发明主要针对AD记忆障碍的病理机制，有效 增加AD大脑神经元钙调蛋白(Calmodulin,CaM)乙酰化及CaMKIIα/GluR1磷酸 化水平，增强相关学习记忆，进而缓解AD记忆障碍。
本领域的技术人员可以明确，在不脱离本发明的总体精神以及构思的情形 下，可以做出对于以上实施例的各种变型。其均落入本发明的保护范围之内。 本发明的保护方案以本发明所附的权利要求书为准。
Claims (10)
1.去乙酰化酶HDAC9在治疗记忆力障碍中作为抑制靶点的应用。
2.去乙酰化酶HDAC9的活性抑制剂在制备记忆力障碍疾病药物中的应用。
3.根据权利要求2所述的应用，其中，所述记忆力障碍疾病包括空间记忆障碍、新物体识别障碍和场景记忆障碍。
4.根据权利要求2所述的应用，其中，所述记忆力障碍疾病包括AD记忆力障碍。
5.根据权利要求2-4任一所述的应用，其中，去乙酰化酶HDAC9活性抑制剂的作用表现为
A.促CaM乙酰化，
B.促CaM下游CaMKIIα磷酸化，
C.促CaMKIIα下游GluR1磷酸化。
6.根据权利要求2-4任一所述的应用，其中，所述去乙酰化酶HDAC9的活性抑制剂包括TMP269。
7.CaM乙酰化水平检测试剂或HDAC9表达水平检测剂在制备阿尔茨海默病检测产品中的应用。
8.根据权利要求7所述的应用，其中，所述阿尔茨海默病为AD记忆力障碍。
9.HDAC9在制备体外CaM蛋白乙酰化制剂非诊断治疗的应用，或HDAC9活性抑制剂在制备治疗CaM蛋白乙酰化异常诱发病症药物中的应用。
10.根据权利要求9所述的应用，其中，所述CaM蛋白为His-Ac-3K-CaM、His-Ac-K22/K95/K116-CaM中任一。
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