载脂蛋白E4参与2型糖尿病认知功能障碍的作用机制及相关标志物的临床意义

Cognitive impairment (CI) is the most common chronic complication of type 2 diabetes mellitus (T2DM), which is seriously affecting the quality of life of T2DM. Studies have shown that insulin resistance (IR) and mitochondrial dysfunction in central nervous system (CNS) may be the key events in the CI with T2DM. However, the mechanism of CI with T2DM is not yet clear, and there is no biomarker to identify who with T2DM will develop CI. Recent studies have found that: ApoE4 impaired insulin signal in neurons and lead to IR, and which was also associated with the mitochondrial dysfunction. Our previous study have showed that the T2DM patients who carried ApoE ε4 had a higher proportion for inducing CI, and accompanied by the mitochondrial dysfunction. Based on the previous work and the reported that ApoE4 could down-regulate the expression of the silent information regulation 2 homolog 1(SIRT1), which is involved in the regulation of mitochondrial biosynthesis, here we hypothesized that ApoE4 could regulate the expression of SIRT1 and further affect the synthesis of mitochondrial DNA, trigger mitochondrial dysfunction and worsened IR, lead to the occurrence of CI with T2DM. In this study, we will explore the mechanisms of ApoE4 in the occurrence of T2DM-CI by the animal and cell’s T2DM models, then collect the clinical cases of T2DM to find biomarkers that could be used for early screening of CI with T2DM, which will provide useful evidences for come out the precision diagnosis and early prevention of CI with T2DM.

认知功能障碍（CI）是2型糖尿病（T2DM）的慢性并发症，严重影响患者的生活质量。研究显示：脑内胰岛素抵抗（IR）及线粒体功能异常，可能是T2DM并发CI的关键事件。具体机制及哪些T2DM患者更易发生CI？目前尚不明确。新近研究发现：载脂蛋白E4（ApoE4）可损伤神经元的胰岛素信号导致IR，同时与线粒体功能异常的发生密切相关。我们前期研究显示：携带ApoE4的T2DM患者发生CI的比例增高，且伴有线粒体功能异常。基于前期工作和ApoE4可下调沉默信息调节蛋白1（SIRT1）；SIRT1可调控线粒体生物合成等报道。我们推测：ApoE4通过调控SIRT1影响线粒体DNA合成，引发线粒体功能异常并加剧IR，参与T2DM性CI发生。本项目拟采用体内体外模型探寻ApoE4在T2DM性CI发生中的作用机制，并收集临床病例，寻找早期筛选T2DM性CI的生物标志物，为其精准检验诊断和有效预防提供依据。

认知功能障碍（CI）是2型糖尿病（T2DM）的慢性并发症之一，严重影响患者的生活质量。已有研究显示：脑内胰岛素抵抗（IR）及线粒体功能异常可能是T2DM认知功能障碍（T2DM-CI）的关键事件。而载脂蛋白E4（ApoE4）作为阿尔茨海默病（AD）的主要遗传危险因子，新近发现其可损伤神经元的胰岛素信号导致IR，同时与线粒体功能异常的发生密切相关，而调沉默信息调节蛋白1（SIRT1）可调控线粒体生物合成，进而影响线粒体功能。但对于ApoE4在T2DM-CI中的作用及其机制尚不明确。本研究分别利用体外过表达ApoE4建立T2DM细胞模型和链脲佐菌素联合高热量饮食诱导的ApoE4转基因小鼠T2DM模型，探寻ApoE4在T2DM-CI发生中的作用及其机制，并探寻可用于筛选T2DM-CI高危个体的可靠生物标志物。我们的研究结果表明：ApoE4是T2DM-CI的遗传危险因素，与T2DM非认知功能障碍患者（T2DM-nCI）相比，T2DM-CI患者ApoE4基因的携带比例明显增加。体内体外研究均证实，线粒体功能异常是T2DM-CI的关键病理事件。ApoE4通过下调SIRT1的表达，影响线粒体生物合成，导致线粒体数目和功能异常；而SIRT1的表达异常可进一步引发胰岛素信号传导通路的异常，加剧IR发生，协同参与T2DM-CI的发生。当给予SIRT1激活剂干预后，上述病理改变可明显改善，进一步提示SIRT1是ApoE4引发T2DM-CI发生的关键靶分子。检测T2DM患者的ApoE基因型，联合外周血认知功能障碍和线粒体功能相关指标对T2DM -CI的具有良好的诊断效能，有望成为临床筛选T2DM-CI的有效手段。综上，本研究通过初步阐明了ApoE4在T2DM-CI发生中的作用及其机制，并评估了ApoE4基因检测联合其他实验指标在筛选T2DM-CI患者中的临床应用价值，为T2DM-CI的精准防治提供了理论和实验依据。