Role of apoE-apoER2 interactions in CNS neurons

项目摘要 载脂蛋白E（apoE 4）的ε4等位基因是晚发性散发性肝癌最重要的遗传危险因素， 阿尔茨海默病（LOAD）。ApoE是一种分泌型糖蛋白，可与许多单通道 低密度脂蛋白受体家族的跨膜受体，包括apoER 2（正式基因名称 = LRP 8）。有趣的是，人apoER 2受到高度的选择性剪接事件的影响， 与外显子跳跃剪接事件相关的前10个神经元基因之一。我们已经确定， 证实了大量的选择性剪接apoER 2受体在人脑中的表达，许多 其含有不同数目的配体结合结构域，所述配体结合结构域改变人apoE蛋白与 载脂蛋白ER 2。然而，差异apoE-apoER 2相互作用的功能后果，下游 这些天然存在的人apoER 2剪接变体的受体信号传导和神经元功能仍然存在 不完全理解。该提案的目标是定义特定apoE的功能后果- apoER 2相互作用可能对我们理解突触可塑性相关的 与学习和记忆以及apoE 4在LOAD中的作用。

PROJECT SUMMARY The ε4 allele of apolipoprotein E (apoE4) is the most important genetic risk factor for late-onset sporadic Alzheimer's disease (LOAD). ApoE is a secreted glycoprotein that binds to a number of single-pass transmembrane receptors of the low-density-lipoprotein receptor family, including apoER2 (official gene name = LRP8). Interestingly, human apoER2 is subject to a high degree of alternative splicing events and notably one of the top 10 of all neuronal genes related to exon-skipping splicing events. We have identified and confirmed the expression of a large number of alternatively spliced apoER2 receptors in human brain, many of which contain a different number of ligand binding domains which alter the binding of human apoE protein to apoER2. However, the functional consequences of differential apoE-apoER2 interactions, downstream receptor signaling and neuronal function for these naturally occurring human apoER2 splice variants remain incompletely understood. The goal of this proposal is to define the functional consequences of specific apoE- apoER2 interactions that could have major implications for our understanding of synaptic plasticity associated with learning and memory and the role of apoE4 in LOAD.