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等位基因是发展阿尔茨海默氏症的强大风险因素之一疾病（AD）。几条证据表明，内体贩运蛋白在大脑中的增加 Apoe E4等位基因载体在认知能力下降开始前数十年。但是，我们的了解APOE4蛋白调节内体贩运的关键机制。这 ATP结合盒1（ABCA1）的活性在脂质贫苦apoE的内吞作用中具有重要作用启动其内体回收。这有助于APOE的脂质及其回收利用到细胞外空间。 ABCA1活性的丧失会增加脂肪贫乏和骨料颗粒。在人类中，遗传功能丧失 ABCA1中的突变与AD风险增加有关。我们假设脂肪贫乏的apoe4的聚集是内体贩运失调的根源，而ABCA1的激活使APOE降低了聚集并有利于其内体回收。为了解决这一假设，我们提出以下三个具体目标。在AIM 1中，我们确定APOE和ABCA1活性如何调节内体的机制贩运原发性星形胶质细胞，神经元和小胶质细胞。在AIM 2中，我们确定衰老的效果，APOE4 基因型并增强ABCA1在APOE聚集和内体运输途径上的活性 APOE靶向替换小鼠，以及在现有的特征良好的人脑组织中，APOE不同基因型和认知状态。在AIM 3中，我们建议开发18-F CS-6253 PET成像方式来评估 APOE E4和衰老对体内ABCA1脑活动的影响。实现我们的目标将提供详细的了解APOE4对内体运输蛋白的影响，证明了一个新颖的概念 ABCA1的激活可以改善含有内体的APOE4的拥塞。获得的信息了解早期事件具有易感性病理和发展的早期事件具有重要意义治疗策略的重点是增强ABCA1活动。