Interplay between meningeal lymphatics, high-density lipoproteins and border macrophages in cerebral amyloid angiopathy

脑淀粉样血管病中脑膜淋巴管、高密度脂蛋白和边界巨噬细胞之间的相互作用

• 批准号: 10674681
• 负责人: Gwendalyn J Randolph
• 金额: $ 57.84万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674681
• 关键词: ATP binding cassette transporter 1; Address; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Behavior; Bile fluid; Blood; Blood Circulation; Blood Vessels; Blood flow; Brain; Cell membrane; Cells; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cholesterol; Chronic; Coupling; Data; Dendritic Cells; Deposition; Disease; Disease Progression; Endocytosis; Experimental Models; Genetic; Health; High Density Lipoproteins; Hour; Human; Image; Impairment; Investigational Therapies; Knock-in Mouse; Laboratories; Leptomeninges; Lesion; Light; Link; Lipoproteins; Liquid substance; Literature; Liver; Lymph; Lymphatic; Macrophage; Mediating; Mediator; Membrane Transport Proteins; Meningeal; Meningeal lymphatic system; Meninges; Modeling; Mus; Natural Immunity; Organ; Penetration; Peptides; Phagocytosis; Phenotype; Plasma; Process; Proteins; Role; Signal Transduction; Site; Testing; Therapeutic Intervention; Thinness; Tissues; Tunica Adventitia; Vascular Diseases; abeta deposition; apolipoprotein E-4; arteriole; blood-brain barrier crossing; brain parenchyma; confocal imaging; cranium; epidemiology study; improved; interest; interstitial; intravital imaging; lymph flow; lymphatic circulation; lymphatic vasculature; monocyte; mouse model; neuroimmunology; porcine model; restraint; reverse cholesterol transport; spatial relationship; tool; trafficking; two-photon; vascular inflammation; β-amyloid burden

ABSTRACT – project 3 The Randolph lab studies vascular inflammation and has a long-standing interest in the egress of cells and molecules that impact chronic vascular diseases. With a track record in studying the trafficking of monocytes (and the cells they become), we later began studying the transit of apoA1-enriched high-density lipoprotein (HDLA1) through tissues. We demonstrated that liver-derived HDLA1 leaves most tissue parenchyma through lymphatics to mediate reverse cholesterol transport, a process whereby cholesterol from cells in various body organs is picked up by HDLA1 and returned to the liver for disposal in bile. Reverse cholesterol transport regulates macrophage phenotype in various diseases, as macrophages readily accumulate cholesterol. On the other hand, macrophages also efficiently transfer cholesterol to HDLA1 via the membrane transporter ABCA1 in a process called cholesterol efflux. If cholesterol efflux is impaired, for example from reduction of HDLA1, cholesterol accumulates in signaling domains at the plasma membrane to affect the phenotype and activation status of macrophages. Overall, macrophages and lymphatics provide two distinct means for tissue clearance of metabolites, debris, and other mediators--one via endocytosis or phagocytosis and the other via fluid transport--and HDLA1 bridges these mechanisms. We have developed and validated a knock-in mouse line expressing photoactivatable GFP linked to apoA1, to quantitatively track endogenous HDLA1 after photo- activating a tissue of interest. Although little HDLA1 crosses the blood-brain barrier to enter the brain, HDLA1 enters the meningeal interstitium. Indeed, preliminary data reveal that the HDLA1 can be tagged by shining 405 nm light on the thinned skullbone as the HDLA1 passes through the meninges. Phototagged meningeal HDLA1 reaches the blood circulation one hour later, but only under conditions when the meningeal draining lymphatic vasculature is intact. Epidemiological studies in cerebral amyloid angiopathy (CAA), a disease broadly associated with Alzheimer’s disease (AD) and characterized by A deposition in the adventitia of the penetrating and meningeal arterioles, identify HDLA1 levels as inversely correlated with cerebral hemorrhage associated with CAA. A connection between HDLA1 and CAA is directly supported by genetic and experimental therapeutic interventions in mice. However, detailed mechanistic studies to unravel how HDLA1 affects CAA have not been conducted. Using the 5XE4fl/fl murine model of CAA developed by the Holtzman laboratory, we will herein focus on unraveling the role of HDLA1 in CAA by coupling use of our HDLA1 phototag tool with approaches to interrogate its connection to lymphatic and blood flow (aim 1), to monocyte/macrophage phenotype (aim 2), and to disease progression overall (aim 3). We here will test the hypothesis that HDLA1 restrains CAA and that its meningeal transit is impaired during CAA. By contrast, in states of health, we propose that it functionally maintains meningeal interstitial flow into lymphatics by interacting with and governing the phenotype of meningeal macrophages, including parenchymal border macrophages (PBM).

摘要 - 项目3 兰道夫实验室研究血管感染，并对细胞出口和 影响慢性血管疾病的分子。在研究单核细胞贩运方面有记录 （以及它们成为的细胞），我们后来开始研究富含ApoA1的高密度脂蛋白的转运 （HDLA1）通过组织。我们证明了肝脏衍生的HDLA1使大多数组织通过 淋巴管介导反向胆固醇转运的淋巴机，从而从各种体内的细胞中胆固醇 器官被HDLA1捡起，并返回肝脏以胆汁处置。反向胆固醇运输 随着巨噬细胞容易积累胆固醇，调节各种疾病中的巨噬细胞表型。在 另一方面，巨噬细胞还通过膜转运蛋白ABCA1有效地将胆固醇转移到HDLA1中 一个称为胆固醇外排的过程。如果胆固醇外排受到损害，例如，HDLA1的减少。 胆固醇在质膜处积聚在信号域中，以影响表型和激活 巨噬细胞的状态。总体而言，巨噬细胞和淋巴管为组织间隙提供了两种不同的手段 代谢物，碎片和其他介体的构成 - 一种是通过内吞作用或吞噬作用，另一种是通过液体 运输 - HDLA1桥接这些机制。我们已经开发并验证了一条敲门鼠标线 表达与apoA1相关的光活性GFP，以定量跟踪内源性HDLA1。 激活感兴趣的组织。尽管很少的HDLA1越过血脑屏障进入大脑，但HDLA1 进入脑膜间质。实际上，初步数据表明，可以通过Shining 405标记HDLA1 当HDLA1穿过脑膜时，NM在稀薄的Skullbone上亮起。光吸收脑膜HDLA1 一小时后达到血液循环，但仅在脑膜排干淋巴的条件下 脉管系统完好无损。脑淀粉样血管病（CAA）的流行病学研究广泛 与阿尔茨海默氏病（AD）相关，并以A沉积为特征 穿透性和脑膜动脉，识别HDLA1水平与脑出血成反比 与CAA相关。 HDLA1和CAA之间的联系直接由遗传和实验支持 小鼠的治疗干预措施。但是，详细的机理研究以解开HDLA1如何影响CAA 尚未进行。使用Holtzman实验室开发的CAA的5XE4FL/FL鼠模型，我们 将通过将HDLA1 phototag工具与使用HDLA1在CAA中的作用有关，将重点放在此处。 询问其与淋巴和血流的联系（目标1），与单核细胞/巨噬细胞的联系 表型（AIM 2）和整体疾病进展（AIM 3）。我们在这里将测试HDLA1的假设 约束CAA，其脑膜运输在CAA期间受到损害。相比之下，在健康状态下，我们 提议通过与和 管理脑膜巨噬细胞的表型，包括实质边界巨噬细胞（PBM）。