ApoE, ABCA1 and endosomal dysregulation in AD

摘要 衰老和携带载脂蛋白E e4等位基因是发生迟发性阿尔茨海默病的最强风险因素之一 疾病（AD）。几条证据显示，脑内的内体运输蛋白增加， APOE e4等位基因携带者在认知能力下降发生前数十年。然而，我们在这方面有一个很大的差距。 了解ApoE 4蛋白调节内体运输的关键机制。的 ATP结合盒1（ABCA 1）的活性在贫脂ApoE的内吞作用中起重要作用， 启动其内体再循环。这有助于ApoE的脂化及其再循环到细胞外空间。 ABCA 1活性的丧失增加了脂质贫乏和聚集的ApoE颗粒。在人类中，基因功能丧失 ABCA 1突变与AD风险增加相关。我们假设低脂ApoE 4的聚集 是核内体运输失调的根源，ABCA 1激活使ApoE脂化， 聚集并有利于其内体再循环。为了解决这一假设，我们提出以下三点 具体目标。在目的1中，我们确定了ApoE和ABCA 1活性如何调节内体细胞的机制， 运输初级星形胶质细胞、神经元和小胶质细胞。在目标2中，我们确定了衰老的影响，APOE 4 基因型和增强ABCA 1活性对ApoE聚集和内体运输途径的影响 ApoE靶向替代小鼠，以及在现有的充分表征的人类脑组织中， 基因型和认知状态。在目标3中，我们建议开发一种18-F CS-6253 PET成像模式来评估 APOE e4和衰老对体内ABCA 1脑活性的影响。实现我们的目标将提供详细的 了解APOE 4对内体运输蛋白的影响，证明了一个新的概念， ABCA 1的活化可改善含有ApoE 4的内体的充血。获得的信息 对于了解易患AD病理和发展的早期事件具有重要意义 治疗策略集中于增强ABCA 1活性。

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.