ApoE, ABCA1 and endosomal dysregulation in AD

AD 中的 ApoE、ABCA1 和内体失调

基本信息

批准号：
10356167
负责人：
Hussein N Yassine
金额：
$ 71.73万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10356167
关键词：
Address Affect Affinity Aging Agonist Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Animal Model Apolipoprotein E Astrocytes Binding Brain Brain imaging Cell Surface Proteins Cell membrane Cell physiology Cell surface Cognition Cognitive Congestive Early Endosome Endocytosis Endosomes Event Extracellular Space Genotype Glutamate Receptor Harvest High Density Lipoproteins Human Human Genetics Impaired cognition Inferior Insulin Receptor Label Late Onset Alzheimer Disease Lipids Microglia Mus Neurons Pathway interactions Peptides Plant Roots Positron-Emission Tomography Proteins Proteomics Recycling Regulation Risk Factors Role Therapeutic Work abeta deposition age effect animal tissue apolipoprotein E receptor 2 apolipoprotein E-3 apolipoprotein E-4 brain tissue frontal lobe human tissue imaging modality in vivo loss of function mutation mouse model novel overexpression particle protein aggregation protein complex protein transport trafficking

项目摘要

Abstract Aging and carrying the APOE e4 allele are among the strongest risk factors for developing late-onset Alzheimer’s disease (AD). Several lines of evidence reveal an increase in endosomal trafficking proteins in the brains of APOE e4 allele carriers decades before the onset of cognitive decline. However, there is a major gap in our understanding of the critical mechanisms by which the ApoE4 protein regulates endosomal trafficking. The activity of the ATP binding cassette 1 (ABCA1) has an important role in the endocytosis of lipid-poor ApoE to initiate its endosomal recycling. This facilitates lipidation of ApoE and its recycling into the extracellular space. Loss of ABCA1 activity increases lipid-poor and aggregated ApoE particles. In humans, genetic loss-of-function mutations in ABCA1 are associated with increased AD risk. We hypothesize that aggregation of lipid-poor ApoE4 is at the root of endosomal trafficking dysregulation, and that activation of ABCA1 to lipidate ApoE decreases its aggregation and favors its endosomal recycling. To address this hypothesis, we propose the following three Specific Aims. In Aim 1, we determine the mechanisms of how ApoE and ABCA1 activity regulate endosomal trafficking in primary astrocytes, neurons and microglia. In Aim 2, we determine the effect of aging, APOE4 genotype and enhancing ABCA1 activity on ApoE aggregation and endosomal trafficking pathways in brains of ApoE targeted replacement mice, and in existing well-characterized human brain tissues that differ by APOE genotype and cognitive state. In aim 3, we propose to develop an 18-F CS-6253 PET imaging modality to assess the effect of APOE e4 and aging on ABCA1 brain activity in vivo. Achieving our aims will provide a detailed understanding of the effect of APOE4 on endosomal trafficking proteins, demonstrating a novel concept that activation of ABCA1 can ameliorate the congestion of ApoE4 containing endosomes. The information obtained is of major significance to understanding early events that predispose to AD pathology and developing therapeutic strategies focused on enhancing ABCA1 activity.

抽象的衰老和携带 APOE e4 等位基因是罹患迟发性阿尔茨海默病的最强风险因素之一多种证据表明，大脑中的内体运输蛋白有所增加。 APOE e4 等位基因携带者在认知能力下降之前几十年就出现了。了解 ApoE4 蛋白调节内体运输的关键机制。 ATP 结合盒 1 (ABCA1) 的活性在贫脂 ApoE 的内吞作用中发挥重要作用启动其内体循环，这有利于 ApoE 的脂化及其循环到细胞外空间。 ABCA1 活性的丧失会增加人类的脂质贫乏和聚集的 ApoE 颗粒，导致遗传功能丧失。 ABCA1 突变与 AD 风险增加有关。是内体运输失调的根源，而激活 ABCA1 来脂化 ApoE 会降低其为了解决这一假设，我们提出了以下三个假设。具体目标在目标 1 中，我们确定 ApoE 和 ABCA1 活性如何调节内体的机制。原代星形胶质细胞、神经元和小胶质细胞的运输在目标 2 中，我们确定了衰老 APOE4 的影响。基因型和增强 ABCA1 对 ApoE 聚集和脑内体运输途径的活性 ApoE 靶向替代小鼠，以及与 ApoE 不同的现有特征良好的人脑组织在目标 3 中，我们建议开发一种 18-F CS-6253 PET 成像方式来评估。 APOE e4 和衰老对体内 ABCA1 大脑活动的影响将为实现我们的目标提供详细的信息。了解 APOE4 对内体运输蛋白的影响，展示了一个新概念获得的信息显示ABCA1的激活可以改善含有ApoE4的内体的充血。对于理解 AD 病理的早期事件和发展具有重要意义治疗策略侧重于增强 ABCA1 活性。