MicroRNA20a在脑淀粉样血管病相关认知功能障碍中的作用及机制研究

Cognitive impairment is the important clinical presentation of Cerebral amyloid angiopathy (CAA), however, it is still lack a noninvasive method for measuring its presentation and severity. Studies demonstrated that miRNA17-92 cluster regulated the expression of APP protein and the production of Aβ in sporadic Alzheimer’s disease (AD). Our preliminary study also showed that the level of miR-20a¬—the member of the miRNA17-92 cluster—was significantly decreased in CAA patients with cognitive impairments. Therefore, we hypothesize that, compared with those without cognitive impairment, miR20a is specifically decreased in CAA patients with cognitive impairments by regulating the expression of APP and Aβ production. To test the hypothesis, we will measure the plasma level of miR-20a and CSF level of Aβ of the recruited CAA patients and analyze the difference of miR-20a and Aβ in cognitive impairments group (CI) and non-cognitive impairments group (non-CI). To further explore the underlying mechanism, whether the effect of miR20a on the production of Aβ is dependent on its regulation of APP expression will be tested in APP Dutch transgenic mice intracraniallyinjected with AAV-GFP-miR-20a or its inhibitor. Moreover, the amyloid angiopathy will be observed in mice brain to further prove the effect of miR-20a on amyloid deposition in the cerebral vascular system. Our study will illuminate the role of miR-20a on CAA-associated cognitive impairments and provide evidence for early treatment in CAA-associated cognitive impairments in the future.

淀粉样脑血管病（CAA）是以脑小血管壁β淀粉样蛋白（Aβ）沉积为特征的临床疾病。认知功能障碍是CAA主要临床症状之一, 目前CAA认知功能障碍发生具体机制尚不明确。研究表明miRNA17-92家族可通过调控阿尔茨海默氏病患者APP表达影响Aβ的产生，我们前期研究表明此家族成员miR-20a在CAA认知功能障碍患者外周血中明显下调。本研究假设miR-20a 可能通过调控APP的表达或其酶切代谢影响Aβ的产生，影响CAA相关认知功能障碍的发生。我们拟通过病毒载体控制CAA小鼠模型神经元miR-20a的表达，从行为学、组织病理及分子蛋白多个层次揭示miR-20a对Aβ调控作用及其可能机制；并通过检测CAA患者外周血 miR-20a及脑脊液Aβ水平, 从临床上初步验证miR-20a对认知障碍的作用，并分析miR-20a和Aβ的相关性，为将来发展CAA认知功能障碍的生物学标记物奠定基础。

淀粉样脑血管病（CAA）是以脑小血管壁淀粉样蛋白（Abeta）沉积为特征的临床疾病。认知功能障碍是CAA主要临床症状之一, 目前CAA认知功能障碍发生具体机制及预测因素尚不清楚。研究表明miRNA17-92家族可通过调控阿尔茨海默氏病患者APP表达影响Abeta的产生，我们前期研究表明此家族成员miR-20a在CAA认知功能障碍患者外周血中明显下调。本研究假设miR-20a 可能通过调控APP的表达或其酶切代谢影响Aβ的产生，影响CAA相关认知功能障碍的发生。本研究在采用了双转基因小鼠模型APP23/PS1∆S169作为CAA的疾病模型来研究miR-20a对Abeta在病理水平和分子水平的作用，分别对3月（n=5）和6月（n=5）的小鼠脑室注射AAV-miR-20a-3p, 4周后观察小鼠情景记忆改变和Abeta老年斑及产量的改变；结果提示在CAA动物模型中miR-20a-3p对动物情景障碍、Abeta斑形成和Abeta的产量无明显作用。本研究第二部分为临床转化部分，共纳入CAA患者121例，对其中年龄、性别、疾病史等匹配的CAA认知障碍（CAA-MCI）患者36例，CAA非认知障碍（CAA-non-MCI）患者36例，正常人群（CTL）20例外周血中的包括miR-20a-3p、miR-20a-5p、miR-21-5p、miR-206、miR-19a-3p、miR-19a-5p、miR-21-3p、miR-17-5p、miR-17-3p、miR-18a-5p和miR-18a-3p在内的miRNA进行检测。研究发现，在miRNA-21-5p中，CAA-MCI（CAA伴认知功能障碍）患者同CAA-non-MCI（CAA不伴认知功能障碍）患者有显著差异（0.071 vs. 0.952 ; P=0.003），此外CAA-MCI和健康人群也存在显著差异（0.071 vs. 1.150; P=0.002；图4）；提示miR-21-5p有潜力作为预测CAA患者中认知功能障碍的发生的新的生物标志物。

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