Unraveling ApoE4 Promotion of Cardiometabolic Disease

项目总结/摘要 晚发性阿尔茨海默病（AD）的最大遗传危险因素是载脂蛋白ε4等位基因 E（apoE）或apoE 4。在我们的父R 01项目中，题为“解开ApoE 4促进心脏代谢”， 我们在小鼠中发现，apoE 4通过内皮细胞中的apoE受体apoER 2发挥作用 减弱内皮胰岛素向骨骼肌的转运，引起外周胰岛素抵抗。我们有 还发现apoE 4是促血栓形成的，很可能也是通过内皮细胞介导的过程， 载脂蛋白ER 2。我们正在测试是否通过碱基编辑将肝脏中的apoE 4遗传校正为apoE 3。 逆转apoE 4对外周胰岛素抵抗和血栓形成的负面影响。新发现的 载脂蛋白E4对内皮胰岛素转运和血栓形成的不利影响可能与血管内皮细胞的凋亡密切相关。 apoE 4对AD的影响因此，在行政补充项目中，我们建议确定 如果通过内皮apoER 2，apoE 4损害CNS胰岛素递送和作用，并促进CNS微血管 血栓形成我们还建议确定在肝脏中apoE 4到apoE 3的碱基编辑是否可以防止不良的免疫反应。 apoE 4在CNS中的作用这样做将确定肝脏来源的apoE 4如何影响CNS中的过程， 并且还提供了一种潜在的手段来预防由apoE 4引起的CNS中的不利过程，而不需要 在CNS内进行干预。行政补充项目的积极成果将导致新的和 一个独特的未来R 01项目，在该项目中，我们在AD小鼠模型中确定了所揭示的机制， 有助于apoE 4对AD病理特征和AD相关认知功能损害的不利影响 功能在未来的项目中，我们将进一步确定肝脏中apoE 4到apoE 3的碱基编辑是否逆转 apoE 4对AD的影响因此，从我们的母公司R 01项目的最新发现出发， 行政补充项目将使我们能够利用我们在内皮细胞生物学方面的专业知识， 关于与AD相关的apoE 4作用的新见解以及否定它们的可能方法。

Project Summary/Abstract The greatest genetic risk factor for late-onset Alzheimer’s disease (AD) is the ε4 allele of apolipoprotein E (apoE), or apoE4. In work in our parent R01 project entitled “Unraveling ApoE4 Promotion of Cardiometabolic Disease” we have discovered in mice that apoE4 actions via the apoE receptor apoER2 in endothelial cells attenuate endothelial insulin transport to the skeletal muscle to cause peripheral insulin resistance. We have also discovered that apoE4 is prothrombotic, most likely also through processes mediated by endothelial apoER2. We are in the process of testing if genetic correction of apoE4 to apoE3 in the liver by base editing reverses the negative impact of apoE4 on peripheral insulin resistance and thrombosis. The newly-discovered adverse effects of apoE4 on endothelial insulin transport and thrombosis may be critically involved in the detrimental impact of apoE4 on AD. Therefore, in the administrative supplement project we propose to determine if via endothelial apoER2, apoE4 impairs CNS insulin delivery and action and promotes CNS microvascular thrombosis. We also propose to determine if base editing of apoE4 to apoE3 in the liver prevents the adverse effects of apoE4 in the CNS. Doing so will determine how liver-derived apoE4 impacts processes in the CNS, and also provide a potential means to prevent adverse processes in the CNS caused by apoE4 without requiring intervention within the CNS. Positive results in the administrative supplement project will lead to a new and unique future R01 project in which we determine in a mouse model of AD how the revealed mechanisms contribute to the adverse impact of apoE4 on AD pathologic features and AD-related impairment in cognitive function. In the future project we will additionally determine if base editing of apoE4 to apoE3 in the liver reverses the detrimental effects of apoE4 on AD. Thus, springboarding from recent discoveries in our parent R01 project, the administrative supplement project will allow us to leverage our expertise in endothelial cell biology to gain new insights about apoE4 actions relevant to AD and possible means to negate them.