Role of apoE-apoER2 interactions in CNS neurons

项目总结 载脂蛋白E(ApoE4)的ε4等位基因是晚发性散发性疾病最重要的遗传危险因素 阿尔茨海默病(LOAD)。载脂蛋白E是一种分泌型糖蛋白，与许多单次通过的 低密度脂蛋白受体家族的跨膜受体，包括ApoER2(官方基因名称 =LRP8)。有趣的是，人类ApoER2受到高度选择性剪接事件的影响，值得注意的是 在所有与外显子跳跃剪接事件有关的神经基因中，排名前十的基因之一。我们已经确定并 证实人脑中有大量选择性剪接的ApoER2受体的表达，其中许多 它们包含不同数量的配基结合域，这些配基结合域改变人载脂蛋白与 ApoER2.然而，不同的apoE-ApoER2相互作用的功能后果，下游 这些自然产生的人类ApoER2剪接变异体的受体信号和神经元功能仍然存在 不完全理解。本提案的目标是定义特定apoE的功能后果- ApoER2的相互作用可能对我们理解与突触可塑性相关的重要意义 与学习和记忆以及载脂蛋白E4在负荷中的作用有关。

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.