Assessing the role of APOE in glial lipid droplet metabolism and function

摘要 阿尔茨海默病(AD)是导致老年人残疾和依赖的主要原因之一 人，是美国第六大死因。迟发性AD是最常见的形式， 超过99%的AD病例发生在65岁之后。发育的最强遗传风险因素 晚发性阿尔茨海默病携带APOE4等位基因。载脂蛋白E(APOE)主要由脑胶质细胞表达。 是星形胶质细胞和小胶质细胞分泌的脂蛋白颗粒的主要蛋白质成分。 脂蛋白颗粒为神经胶质细胞和神经元之间的脂类双向运输提供了一种机制。许多 最近的研究表明，神经系统血脂的失衡与患高血压的风险增加有关。 开发AD。然而，APOE4影响细胞内脂平衡的机制是 不完全理解。我们最近发现，在胶质细胞中，载脂蛋白E可以运输到细胞质的脂滴 (LDS)，而不是在脂蛋白颗粒上分泌。我们假设APOE之前玩过 通过直接作用于星形胶质细胞和小胶质细胞中的LDS，在细胞脂质代谢中发挥未知的作用。 星形胶质细胞在过氧化脂质代谢中起着重要作用，而小胶质细胞是主要的先天细胞。 中枢神经系统的免疫效应细胞。在目标1中，我们将测试调制APOE的效果 星形胶质细胞对细胞脂质组成、代谢和脂质过氧化的影响。在目标2中，我们将测试效果 小胶质细胞载脂蛋白E对细胞脂组成、代谢和炎症的调节作用。在目标3中，我们 将通过开发社区资源以可视化和量化各种类型的LD来填补关键的知识缺口 不同基因和年龄小鼠的脑区和细胞类型。总之，这些研究将导致 关于APOE4表达增加的细胞和分子机制的新见解 晚发性AD的风险。这项工作还可能导致确定新的药物靶点，以预防和 治疗老年痴呆症。

ABSTRACT Alzheimer’s disease (AD) is one of the predominant causes of disability and dependency among older people, and the sixth leading cause of death in the United States. Late-onset AD is the most common form, with more than 99% of AD cases occurring after age 65. The strongest genetic risk factor for developing late-onset AD is carrying the APOE4 allele. Apolipoprotein E (APOE) is primarily expressed by glial cells in the brain and is the major protein component of lipoprotein particles secreted by astrocytes and microglia. Lipoprotein particles provide a bidirectional mechanism of lipid transport between glia and neurons. Many recent studies suggest that a disequilibrium in nervous system lipids is associated with increased risk of developing AD. However, the mechanisms by which APOE4 affects cellular lipid homeostasis are incompletely understood. We recently discovered that in glia, APOE can traffic to cytoplasmic lipid droplets (LDs) rather than undergoing secretion on lipoprotein particles. We hypothesize that APOE plays previously unrecognized roles in cellular lipid metabolism by acting directly on LDs in astrocytes and microglia. Astrocytes play important roles in metabolizing peroxidated lipids, while microglia are the primary innate immune effector cells of the central nervous system. In Aim 1, we will test the effect of modulating APOE in astrocytes on cellular lipid composition, metabolism, and lipid peroxidation. In Aim 2, we will test the effect of modulating APOE in microglia on cellular lipid composition, metabolism, and inflammation. In Aim 3, we will fill a key knowledge gap by developing a community resource visualizing and quantifying LDs in various brain regions and cell types in mice of different genotypes and ages. Together, these studies will lead to new insights about the cellular and molecular mechanism by which expression of APOE4 leads to increased risk of late-onset AD. This work could also lead to the identification of novel drug targets for preventing and treating AD.