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

评估 APOE 在神经胶质脂滴代谢和功能中的作用

基本信息

批准号：
10645540
负责人：
Sarah Cohen
金额：
$ 58.56万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10645540
关键词：
Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloidosis Apolipoprotein E Area Astrocytes Brain Brain region Cause of Death Cell Death Cellular biology Central Nervous System Code Communities Cytoplasm Data Data Set Databases Dementia Dependence Deposition Drug Targeting Educational workshop Effector Cell Elderly Endoplasmic Reticulum Fluorescence-Activated Cell Sorting Future Genotype Glycolysis Homeostasis Image Immune Inflammation Inflammatory Investigation Knockout Mice Knowledge Late Onset Alzheimer Disease Lipid Peroxidation Lipids Lipoproteins Metabolism Microglia Microscopy Molecular Mus Natural Immunity Nerve Degeneration Nervous System Neuroglia Neurons Pathway interactions Play Protein Isoforms Proteins Research Resources Risk Role Surface Testing Therapeutic United States Visualization Work aging brain apolipoprotein E-4 brain cell cell type cytokine disability genetic risk factor in vivo insight laboratory experience lipid metabolism lipid transport mouse model new therapeutic target normal aging novel particle prevent trafficking

项目摘要

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.

抽象的阿尔茨海默病（AD）是老年人残疾和依赖的主要原因之一人，并且晚发性 AD 是最常见的形式，超过 99% 的 AD 病例发生在 65 岁之后。晚发型 AD 携带 APOE4 等位基因，主要由神经胶质细胞表达。是大脑中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。脂蛋白颗粒提供了神经胶质细胞和神经元之间的双向脂质运输机制。最近的研究表明，神经系统脂质的不平衡与以下疾病的风险增加有关：然而，APOE4 影响细胞脂质稳态的机制是：我们最近发现，在神经胶质细胞中，APOE 可以运输到细胞质脂滴。（LD）而不是在脂蛋白颗粒上进行分泌我们认为 APOE 以前发挥过作用。通过直接作用于星形胶质细胞和小胶质细胞中的 LD，在细胞脂质代谢中发挥未被识别的作用。星形胶质细胞在过氧化脂质代谢中发挥重要作用，而小胶质细胞是主要的先天性代谢途径。在目标 1 中，我们将测试调节 APOE 的效果。在目标 2 中，我们将测试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 3 中，我们研究了调节小胶质细胞中的 APOE 对细胞脂质组成、代谢和炎症的影响。将通过开发可视化和量化各种 LD 的社区资源来填补关键知识空白这些研究将共同研究不同基因型和年龄的小鼠的大脑区域和细胞类型。关于 APOE4 表达导致细胞和分子机制增加的新见解这项工作还可能有助于确定预防和治疗迟发性 AD 的新药物靶点。治疗AD。