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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要脑毛细血管由单层内皮细胞组成，上面覆盖着称为“毛细血管”的特殊壁细胞。周细胞和内皮细胞之间的通讯对于脑毛细血管的健康至关重要。研究表明，阿尔茨海默氏病和血管性痴呆涉及死亡或退化的增加这被认为会导致血脑屏障完整性和大脑损伤。血流量，随后加剧神经退行性变，因此，需要采取缓解或缓解的策略。补偿周细胞覆盖的损失可能有助于保护这些神经系统的血管功能我们最近发现大脑周细胞具有在成人大脑中进行结构重塑的能力。为了响应体内单个周细胞的局部消融，我们观察到过程的稳健扩展邻近的周细胞，可以到达大片毛细血管床以重新与周围细胞接触在年轻的健康小鼠中，周细胞覆盖的短暂丧失导致了持续性毛细血管的形成。扩张和异常高的血细胞通量，直到周细胞重新接触。这些发现表明。周细胞重塑是一种补偿周细胞损失的修复机制。能力随着年龄的增长而减弱，并在脑淀粉样蛋白沉积过程中因淀粉样蛋白沉积而进一步受损血管病是阿尔茨海默病中常见的小血管疾病。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蛋白小鼠的周细胞动态在目标 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，毛细血管淀粉样蛋白沉积物表现出独特的富集作用。在目标 2 中，我们将使用一种新颖的方法。专为双光子成像而设计的氧敏感探针，以更好地了解周细胞的后果该项目将揭示一个很大程度上未被研究的方面。周细胞生物学可能会带来增强周细胞-内皮接触和保护大脑的新方法它将通过以下方式推进该领域的发展：1）表征周细胞的动态。使用体内光学成像进行详细重塑，2）提供有关小血管疾病如何损害血管的见解脑毛细血管的修复能力，3）促进研究周细胞的新工具的开发活体小鼠大脑中前所未有的特异性。