Role of apoE-apoER2 interactions in CNS neurons

apoE-apoER2 相互作用在 CNS 神经元中的作用

基本信息

批准号：
10213620
负责人：
Uwe Beffert
金额：
$ 48.46万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213620
关键词：
Adult Affect Affinity Alleles Alternative Splicing Alzheimer&apos s Disease Apolipoprotein E Binding Biological Assay Brain C-terminal Characteristics Complex Data Development Electrophysiology (science)Epigenetic Process Event Family Gene Expression Profile Generations Genes Genetic Transcription Glycoproteins Goals Human Impaired cognition Integral Membrane Protein Late Onset Alzheimer Disease Learning Ligand Binding Ligand Binding Domain Ligands Link Location Low Density Lipoprotein Receptor Mass Spectrum Analysis Mediating Memory Methods N-Methyl-D-Aspartate Receptors Names Neurons Pathogenesis Pathologic Property Protein Isoforms Proteins RNA Splicing Receptor Signaling Role Signal Transduction Site Spliced Genes Synapses Synaptic plasticity Testing Variant apolipoprotein E receptor 2 apolipoprotein E-3 apolipoprotein E-4 cell type differential expression exon skipping experimental study genetic risk factor global run on sequencing innovation insight mouse model novel receptor receptor function synaptic function

项目摘要

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.

项目概要载脂蛋白 E (apoE4) 的 ε4 等位基因是晚发散发性遗传病最重要的遗传危险因素阿尔茨海默病 (LOAD) 是一种分泌性糖蛋白，可与许多单程蛋白结合。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）。我们已经鉴定出与外显子跳跃剪接事件相关的前 10 个神经元基因之一。证实人脑中存在大量选择性剪接的apoER2受体的表达，其中许多其中含有不同数量的配体结合结构域，可改变人 apoE 蛋白的结合然而，apoE-apoER2 下游相互作用的功能后果这些天然存在的人类 apoER2 剪接变体的受体信号传导和神经元功能仍然存在该提案的目标是定义特定 apoE 的功能后果。 apoER2 相互作用可能对我们理解相关突触可塑性产生重大影响学习和记忆以及 apoE4 在 LOAD 中的作用。