ApoE, ABCA1 and endosomal dysregulation in AD

摘要 衰老和携带APOE e4等位基因是导致迟发性阿尔茨海默病的最大危险因素之一 疾病(AD)。多条证据显示，脑内膜转运蛋白增加。 APOE e4等位基因携带者在认知功能减退开始前几十年。然而，我们有一个很大的差距， 了解载脂蛋白E4蛋白调节内体转运的关键机制。这个 ATP结合盒1(ABCA1)的活性在低脂载脂蛋白E的内吞作用中起着重要作用 启动它的内体循环。这促进了ApoE的脂化和它在细胞外空间的再循环。 ABCA1活性的丧失会增加贫脂和聚集的载脂蛋白E颗粒。在人类中，遗传功能丧失 ABCA1基因突变与AD风险增加相关。我们假设低脂载脂蛋白E4的聚集 是内体转运失调的根源，激活ABCA1来脂化ApoE会降低其 聚集，并有利于其内体循环。为了解决这一假设，我们提出了以下三点 明确的目标。在目标1中，我们确定了ApoE和ABCA1活性如何调节内体的机制 初级星形胶质细胞、神经元和小胶质细胞的运输。在目标2中，我们确定了衰老的影响，APOE4 基因分型和增强ABCA1活性对小鼠脑内载脂蛋白E聚集和内体转运途径的影响 APOE靶向替换小鼠，以及在APOE不同的现有特征良好的人脑组织中 基因分型和认知状态。在目标3中，我们建议开发一种18-F CS-6253 PET成像设备来评估 载脂蛋白e4和衰老对ABCA1脑活动的影响实现我们的目标将提供一个详细的 了解APOE4对内体运输蛋白的影响，展示了一个新的概念 ABCA1的激活可以改善含ApoE4的内小体的充血。所获得的信息 对了解阿尔茨海默病发病的早期事件及其发生发展具有重要意义 治疗策略侧重于增强ABCA1的活性。

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.