Effect of Brain Lymphatic Activation on Alzheimer's Disease Progression

脑淋巴激活对阿尔茨海默病进展的影响

基本信息

批准号：
10540194
负责人：
Young-Kwon Hong
金额：
$ 45.38万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540194
关键词：
Address Agonist Alzheimer&apos s Disease Alzheimer&apos s disease pathology Behavior Biological Blood - brain barrier anatomy Brain Brain Diseases Calcium Channel Cerebrospinal Fluid Chemicals Consequentialism Data Dementia Disease Disease Progression Drainage procedure Dura Mater Ectopic Expression Endothelial Cells Failure Fluid Balance Foundations Genetic Genetic study Growth Health Histopathology In Vitro Intercellular Junctions Ion Channel Kinetics Liquid substance Lymphatic Lymphatic System Lymphatic function Magnetic Resonance Imaging Mediating Meningeal lymphatic system Meninges Molecular Mus Outcome Outcome Study Pathway interactions Pharmacology Physiology Piezo 1 ion channel Preventive Publishing Relaxation Reporting Role Tamoxifen Therapeutic Therapeutic Agents Therapeutic Intervention Tissues Transgenic Model Translating Vascular Endothelial Growth Factor C Work abeta accumulation abeta deposition base brain abnormalities brain dysfunction brain health cognitive function drug candidate fluid flow genetic approach high throughput screening in vivo intervention effect lymphatic drainage lymphatic dysfunction lymphatic vessel mechanical signal mechanotransduction mouse model nervous system disorder new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics response sensor small molecule therapeutic target wasting

项目摘要

PROJECT SUMMARY Failure of brain waste clearance by the cerebrospinal fluid outflow has been associated with various neurological diseases. Disruption of the meningeal lymphatics in Alzheimer's disease (AD) mouse models leads to amyloid- β deposition in the meninges and aggravates parenchymal Aβ accumulation. The 5xFAD mouse model displays impaired lymphatic function and contractility and significantly delayed brain fluid outflow. These results suggest that meningeal lymphatics profoundly contribute to brain fluid homeostasis and that optimal brain fluid drainage is critical for maintaining brain health and function. Consistently, our preliminary studies demonstrate that activation of the brain lymphatics through a mechanosensor Piezo1 expedited the brain fluid outflow in two mouse models with abnormal brain fluid accumulation. Together, we hypothesize that enhancing the brain lymphatic drainage would offer therapeutic benefits to AD. To address this hypothesis, we propose to stimulate the brain lymphatic drainage by genetic (Aim1) and chemical (Aim2) activations of Piezo1, followed by evaluating their effects on the initiation and progression of AD. Together, the outcome of this work will not only identify Piezo1 as a novel target for AD, but also provide a conceptual foundation for enhancing the brain lymphatic drainage as a novel therapeutic approach against various neurological diseases.

项目摘要脑遗传流体溢流流量失败与各种神经系统有关阿尔茨海默氏病（AD）小鼠模型中脑膜淋巴染的破坏导致淀粉样蛋白 β在脑膜中沉积并加剧了副群Aβ的积累。 5xFAD鼠标模型显示淋巴功能和收缩性受损，并显着延迟了脑液出口。这些结果表明脑膜淋巴细胞表对脑液体稳态有深刻的贡献，最佳的脑液排水对于维持大脑健康和功能至关重要。一致地，我们的初步研究表明通过机械力学压电激活脑淋巴机，在两个中加快了脑液出口小鼠模型具有异常的脑液积累。我们一起假设可以增强大脑淋巴引流将为AD带来治疗益处。为了解决这一假设，我们建议刺激遗传（AIM1）和Piezo1化学（AIM2）激活的脑淋巴引流，然后评估它们对AD的主动性和进展的影响。一起，这项工作的结果不仅会确定压电1作为AD的新目标，但也为增强脑淋巴的概念基础提供了概念基础排水作为针对各种神经系统疾病的新型热方法。