APOE effects on glial lipid metabolism and 25-hydroxycholesterol: Effects on aging and AD-related pathology

APOE 对神经胶质脂质代谢和 25-羟基胆固醇的影响：对衰老和 AD 相关病理的影响

基本信息

批准号：
10407944
负责人：
DAVID M. HOLTZMAN
金额：
$ 54.01万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407944
关键词：
25-hydroxycholesterol Affect Age Aging Agonist Alzheimer&apos s Disease Amyloid beta-Protein Amyloid deposition Apolipoprotein E Astrocytes Biochemical Bioinformatics Biological Markers Biology Brain Brain region Cells Cholesterol Cholesterol Esters Cholesterol Homeostasis Coculture Techniques Collaborations Data Defect Demyelinations E protein Gene Expression Genotype Histologic Human Immune Immunomodulators In Vitro Inflammasome Inflammation Inflammatory Response Injections Innate Immune Response Knock-in Knock-in Mouse Knockout Mice Lead Link Lipids Lipoproteins Literature Mass Spectrum Analysis Measures Mediating Microglia Mixed Function Oxygenases Modeling Mus Nerve Degeneration Neuroglia Neurons Pathogenesis Pathology Phenotype Play Process Production Property Protein Isoforms Proteomics Regulation Role Signal Transduction Source Sterols Stimulus Structure Tauopathies Variant Work abeta deposition age related cytokine density glial activation immunoregulation improved in vivo induced pluripotent stem cell lipid metabolism lipidomics metabolomics neuropathology neurotoxicity particle remyelination response reverse cholesterol transport sex tau Proteins

项目摘要

PROJECT SUMMARY (APOE U19: PROJECT 2) Project 2 seeks to improve understanding of how apolipoprotein E (apoE) isoforms influence glial lipid metabolism and inflammatory responses underlying immune-mediated damage in the brain in Alzheimer’s disease (AD) and aging-related pathologies. Evidence indicates that the apoE protein not only affects Aβ deposition and structure, it strongly influences microglial-activation, Aβ-induced neuritic dystrophy, and tau- mediated neurodegeneration. ApoE produced by both astrocytes and microglia plays an important role in these effects, and microglia are critical effectors of neurodegeneration. In alignment with the ApoE Cascade Hypothesis of this U19, we anticipate that structural differences and related biochemical properties among the apoE isoforms are likely to mediate the differential effects of apoE on the brain’s innate immune response. Factors such as lipid metabolism and sterol processing, can influence microglial reactivity in ways that are relevant to AD pathogenesis. Recent evidence indicates that apoE and aging critically influence the process of cholesterol and lipid clearance in the brain, specifically in microglia. Accumulation of lipid debris in microglia under different conditions is linked with microglial activation and inflammasome-mediated damage. There is also literature and we have preliminary data that 25-hydroxycholesterol (25HC), a known oxysterol immunomodulator, is produced in the brain by microglia and can modulate cholesterol metabolism as well as the microglial cytokine response in an apoE isoform-dependent manner in vitro. These data lead us to hypothesize that apoE-dependent regulation and clearance of cholesterol esters and other lipids specifically in microglia regulates the microglial inflammatory response in aging and AD. We further hypothesize that this microglial response including 25HC production impacts Aβ-induced local damage, Aβ- induced tau spreading, and tau-mediated neurodegeneration in an apoE, age, and sex-dependent fashion. We propose these aims: Aim 1: Determine the effects of apoE and apoE isoforms on cholesterol, cholesterol esters, and other lipids in astrocytes and microglia during aging, in the setting of Aβ and tau pathology, and with LXR agonist stimulation. Aim 2: Assess the effects of the immunomodulatory oxysterol, 25- hydroxycholesterol (25HC) on Aβ-mediated tau-spreading, tau-mediated neurodegeneration, and age-related brain phenotypes and how these are modified by apoE. Aim 3: Assess the effect of apoE isoform on the lipidomic profile of astrocytes, microglia, and secreted apoE-containing lipoproteins as well as the mechanistic relationship between lipid droplet formation, apoE signaling, and inflammation in vitro. We will also assess the mechanism of the effects of ch25h on apoE-mediated neurodegeneration in vitro. Impact/Integration: Project 2 will work closely with Projects 1, 3, 5, Core B, Core D, Core E, Core F, and Core G on production, purification, and characterization of apoE particles and lipids from mouse glia in vitro and in vivo and iPSC derived glia in vitro. Histological analysis in Project 2 will be done with the Neuropathology Core (Core C).

项目摘要（APOE U19：项目 2）项目 2 旨在加深对载脂蛋白 E (apoE) 异构体如何影响神经胶质脂质的了解阿尔茨海默病患者大脑免疫介导损伤的代谢和炎症反应证据表明 apoE 蛋白不仅影响 Aβ。沉积和结构，它强烈影响小胶质细胞激活、Aβ 诱导的神经营养不良和 tau- 星形胶质细胞和小胶质细胞产生的 ApoE 在神经退行性变中起着重要作用。这些效应和小胶质细胞是神经退行性变的关键效应器，与 ApoE 级联一致。对于这个U19的假设，我们预计U19之间的结构差异和相关生化特性 apoE 亚型可能介导 apoE 对大脑先天免疫反应的不同影响。脂质代谢和甾醇加工等因素可以通过以下方式影响小胶质细胞的反应性：与 AD 发病机制相关。最近的证据表明，apoE 和衰老对 AD 的过程有重要影响。大脑中胆固醇和脂质的清除，特别是小胶质细胞中脂质碎片的积累。在不同条件下与小胶质细胞激活和炎性体介导的损伤有关。还有文献，我们有初步数据表明 25-羟基胆固醇 (25HC)，一种已知的氧甾醇免疫调节剂，由小胶质细胞在大脑中产生，可以调节胆固醇代谢以及这些数据引导我们在体外以 apoE 同工型依赖性方式进行小胶质细胞细胞因子反应。胆固醇酯和其他脂质的 apoE 依赖性调节和清除特别是在小胶质细胞中，我们进一步调节衰老和 AD 中的小胶质细胞炎症反应。这种小胶质细胞反应，包括 25HC 的产生，会影响 Aβ 诱导的局部损伤，Aβ- 以 apoE、年龄和性别依赖性方式诱导 tau 扩散和 tau 介导的神经变性。这些建议旨在：目标 1：确定 apoE 和 apoE 亚型对胆固醇、胆固醇的影响在 Aβ 和 tau 病理学背景下，衰老过程中星形胶质细胞和小胶质细胞中的酯类和其他脂质，以及目标 2：评估免疫调节氧甾醇 25- 的作用。羟基胆固醇 (25HC) 对 Aβ 介导的 tau 扩散、tau 介导的神经变性和年龄相关的影响目标 3：评估 apoE 异构体对大脑表型的影响。星形胶质细胞、小胶质细胞和分泌的含 apoE 脂蛋白的脂质组学特征以及机制我们还将评估体外脂滴形成、apoE 信号传导和炎症之间的关系。 ch25h 对 apoE 介导的神经变性的体外影响机制：项目。 2 将与项目 1、3、5、Core B、Core D、Core E、Core F 和 Core G 密切合作进行生产，小鼠神经胶质细胞的 apoE 颗粒和脂质的体外和体内以及 iPSC 的纯化和表征项目 2 中的神经胶质细胞体外组织学分析将使用神经病理学核心（核心 C）进行。