The effects of amyloid beta on pericyte remodeling and brain capillary function in vivo

β淀粉样蛋白对体内周细胞重塑和脑毛细血管功能的影响

• 批准号: 9898221
• 负责人: Andy Y Shih
• 金额: $ 23.25万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898221
• 关键词: Ablation; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Basic Science; Biology; Blood; Blood - brain barrier anatomy; Blood Cells; Blood Vessels; Blood capillaries; Blood flow; Brain; Caliber; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrovascular Disorders; Cessation of life; Communication; Crossbreeding; Data; Defect; Deposition; Development; Disease Progression; Endothelial Cells; Endothelium; Exhibits; Future; Health; Human; Image; Impairment; Injury; Knowledge; Label; Lead; Light; Maintenance; Measures; Microscopy; Microvascular Dysfunction; Mus; Nerve Degeneration; Optics; Oxygen; Partial Pressure; Pathology; Pericytes; Physiological; Process; Resolution; Role; Shapes; Specificity; Stretching; Structure; Surface; Testing; Theft; Time; Tissues; United States; Vascular Dementia; Vascular System; Vascular blood supply; Visualization; abeta deposition; age effect; aged; blood-brain barrier permeabilization; brain remodeling; capillary bed; cell type; cerebral capillary; design; experimental group; in vivo; in vivo imaging; in vivo optical imaging; insight; middle age; mouse model; nervous system disorder; novel; novel strategies; pre-clinical; preservation; repaired; response; socioeconomics; therapeutic development; therapeutic target; tissue oxygenation; tool; two photon microscopy; two-photon; young adult

Project Summary Brain capillaries are composed of a single layer of endothelial cells covered by specialized mural cells called pericytes. Communication between pericytes and endothelial cells is essential for brain capillary health. Recent studies indicate that Alzheimer’s disease and vascular dementia involve increased death or degeneration of brain pericytes. This is thought to contribute to the impairment of both blood-brain barrier integrity and cerebral blood flow, which subsequently exacerbates neurodegeneration. Therefore, strategies to mitigate or compensate for loss of pericyte coverage may help to preserved vascular function in these neurological diseases. We recently discovered that brain pericytes have the ability to structurally remodel in the adult brain. In response to focal ablation of single pericytes in vivo, we observed the robust extension of processes from neighboring pericytes, which could reach over large stretches of capillary bed to regain contact with the exposed endothelium. In young healthy mice, the transient loss of pericyte coverage led to persistent capillary dilation and abnormally high blood cell flux, until pericyte contact was regained. These findings suggest that pericyte remodeling is a reparative mechanism to compensate for pericyte loss. We hypothesize that this capacity is diminished with age and further impaired with amyloid deposition during cerebral amyloid angiopathy, a frequent small vessel disease in Alzheimer’s. To address this hypothesis, we plan to use in vivo two-photon microscopy to directly observe pericytes dynamics in normal mice and mice with cerebral amyloid angiopathy. In Aim 1, we will test whether remodeling capacity is reduced in young and aged Tg-SwDI mice, which exhibit a unique enrichment of capillary amyloid deposits over time. In Aim 2, we will use a novel oxygen-sensitive probe designed for two-photon imaging to better understand the consequence of pericyte loss on blood flow and local tissue oxygenation. This project will shed light on a largely unstudied facet of pericyte biology that may lead to novel approaches to augment pericyte-endothelial contact and preserve brain capillary health in Alzheimer’s disease. It will advance the field by: 1) Characterizing the dynamics of pericyte remodeling in detail using in vivo optical imaging, 2) providing insight on how small vessel disease impairs the reparative capacity of brain capillaries, and 3) promoting the development of new tools to study pericytes with unprecedented specificity in the living mouse brain.

项目摘要 大脑毛细血管由单层内皮细胞组成，由特殊的壁细胞覆盖，称为 周细胞。周细胞和内皮细胞之间的通讯对于大脑毛细血管的健康是必不可少的。近期 研究表明，阿尔茨海默病和血管性痴呆涉及增加的死亡或变性 脑周细胞。这被认为是导致血脑屏障完整性和脑损伤的原因之一。 血液流动，这随后加剧了神经退化。因此，减轻或减少风险的战略 补偿周细胞覆盖率的丧失可能有助于保护这些神经病的血管功能 疾病。我们最近发现，脑周细胞具有在成人大脑中进行结构重塑的能力。 作为对体内单个周细胞的局灶性消融的反应，我们观察到从 邻近的周细胞，可以延伸到大范围的毛细血管床上，重新与 裸露的内皮细胞。在年轻健康的小鼠中，周细胞覆盖的短暂丧失导致持续的毛细血管 扩张和异常高的血细胞流量，直到周细胞重新接触。这些发现表明， 周细胞重塑是弥补周细胞丢失的一种修复机制。我们假设这是 能力随着年龄的增长而降低，并在大脑淀粉样蛋白沉积过程中进一步受损 血管病变，阿尔茨海默氏症中一种常见的小血管疾病。为了解决这一假设，我们计划在体内使用 双光子显微镜直接观察正常小鼠和脑淀粉样变小鼠周细胞动力学 血管病。在目标1中，我们将测试年轻和老年TG-Swdi小鼠的重塑能力是否降低， 随着时间的推移，显示出独特的毛细血管淀粉样沉积的丰富。在《目标2》中，我们将用一本小说 用于双光子成像的氧敏探针设计，以更好地了解周细胞的后果 血流丧失和局部组织氧合。这个项目将揭示一个很大程度上未被研究的方面 周细胞生物学可能导致新的方法来加强周细胞与内皮的接触和保存大脑 阿尔茨海默病的毛细血管健康。它将通过以下方式推进该领域：1)表征周细胞的动力学 使用活体光学成像详细重建，2)提供关于小血管疾病如何损害 脑毛细血管的修复能力，以及3)促进研究周细胞的新工具的开发 在活着的小鼠大脑中具有前所未有的专一性。