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

• 批准号: 10667466
• 负责人: DAVID M. HOLTZMAN
• 金额: $ 53.02万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 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/10667466
• 关键词: 25-hydroxycholesterol; Affect; Age; Aging; Agonist; Alzheimer' 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; 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

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旨在提高对载脂蛋白E（APOE）同工型如何影响神经胶质脂质的理解 阿尔茨海默氏症中免疫介导的免疫介导的损害的代谢和炎症反应 疾病（AD）和与衰老有关的病理。证据表明APOE蛋白不仅影响Aβ 沉积和结构，强烈影响小胶质细胞激活，Aβ诱导的神经元营养不良和tau- 介导的神经变性。星形胶质细胞和小胶质细胞产生的APOE在 这些作用和小胶质细胞是神经退行性的关键作用。与Apoe Cascade保持一致 该U19的假设，我们预计结构差异和相关的生化特性 APOE同工型可能会介导APOE对大脑先天免疫反应的差异作用。 脂质代谢和立体声处理等因素可以以类似的方式影响小胶质的反应性 与AD发病机理有关。最近的证据表明，APOE和衰老严重影响 大脑中的胆固醇和脂质清除率，特别是小胶质细胞。小胶质细胞中脂质碎片的积累 在不同的条件下，与小胶质细胞激活和炎症体介导的损伤有关。有 还有文献，我们有25-羟基胆固醇（25HC）的初步数据，一种已知的氧蛋白酶 免疫调节剂是通过小胶质细胞在大脑中产生的，可以调节胆固醇代谢以及 小胶质细胞因子在体外以APOE同工型依赖性方式。这些数据导致我们进入 假设APOE依赖性调节和胆固醇酯和其他脂质的清除率 在小胶质细胞中具体调节衰老和AD中的小胶质细胞炎症反应。我们进一步 假设这种小胶质响应包括25HC产生会影响Aβ诱导的局部损害Aβ- 诱导的tau扩散，tau介导的神经退行性以APOE，年龄和性别依赖性方式。 这些目的：目标1：确定APOE和APOE同工型对胆固醇，胆固醇的影响 在衰老期间，在Aβ和TAU病理学的情况下，酯和其他脂质在衰老过程中以及小胶质细胞中 与LXR激动剂刺激。 AIM 2：评估免疫调节性氧甲醇的影响，25-- 在Aβ介导的tau传播，tau介导的神经变性和与年龄相关的Aβ介导的羟化胆固醇（25HC）上 大脑表型以及如何通过APOE修饰它们。 AIM 3：评估APOE同工型对 星形胶质细胞，小胶质细胞和分泌的含ApoE的脂蛋白以及机械的脂质组谱 脂质液滴形成，APOE信号传导和体外炎症之间的关系。我们还将评估 CH25H对APOE介导的神经变性的作用机理。影响/集成：项目 2将与项目1、3、5，Core B，Core D，Core E，Core F和Core G的生产中紧密合作， 在体外和体内和IPSC中纯化和表征小鼠神经胶质的APOE颗粒和脂质 体外衍生的神经胶质。项目2中的组织学分析将使用神经病理学核心（Core C）进行。