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.

项目摘要脑毛细血管由单层的内皮细胞组成，该细胞被专门的壁画细胞覆盖周细胞。周细胞和内皮细胞之间的通信对于脑毛细血管健康至关重要。最近的研究表明，阿尔茨海默氏病和血管性痴呆涉及增加的死亡或变性脑周细胞。人们认为这会导致血脑屏障完整性和大脑的损害血流，随后加剧了神经变性。因此，减轻或补偿周细胞覆盖范围的损失可能有助于保留这些神经系统的血管功能疾病。我们最近发现，大脑时期具有在成人大脑中进行结构重塑的能力。响应于体内单个周细胞的局部消融，我们观察到了从附近的周细胞，可以在大片毛细管床上到达，以恢复与暴露的内皮。在年轻的健康小鼠中，周细胞覆盖范围的短暂损失导致了持续的毛细管扩张和绝对的高血细胞通量，直到持续过血管接触。这些发现表明周细胞重塑是补偿周细胞损失的一种修复机制。我们假设这是脑淀粉样蛋白期间的淀粉样蛋白沉积会随着年龄的增长而降低能力，并进一步受损血管病，阿尔茨海默氏症经常是小血管疾病。为了解决这一假设，我们计划在体内使用两光子显微镜直接观察正常小鼠和脑淀粉样蛋白的小鼠周细胞动力学血管病。在AIM 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，随着时间的流逝，它表现出独特的毛细血管淀粉样蛋白沉积物的富集。在AIM 2中，我们将使用小说氧气敏感的探针专为两光子成像设计，以更好地了解周细胞的后果血流和局部组织氧合的损失。该项目将揭示在很大程度上未研究的方面周围生物学可能导致新颖的方法来增强周细胞 - 内皮接触并保存大脑阿尔茨海默氏病的毛细血管健康。它将通过：1）表征浮游动力学来推进磁场使用体内光学成像进行详细的重塑，2）提供有关小血管疾病如何损害的见解脑毛细血管的修复能力，以及3）促进开发新工具以研究周细胞活小鼠大脑中空前的特异性。