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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.

项目总结