Effect of Brain Lymphatic Activation on Alzheimer's Disease Progression

项目总结 脑脊液外流导致的脑废物清除失败与多种神经疾病有关 疾病。阿尔茨海默病(AD)小鼠模型脑膜淋巴管的破坏导致淀粉样蛋白- β在脑膜内沉积，加重实质内A-β积聚。显示5xFAD鼠标型号 淋巴功能和收缩功能受损，脑液流出明显延迟。这些结果表明 脑膜淋巴管对脑液动态平衡和最佳脑液引流有重大贡献 对维持大脑健康和功能至关重要。我们的初步研究一贯表明， 通过机械传感器Piezo1激活脑淋巴管加速脑液在两个部位的流出 脑液异常蓄积的小鼠模型。我们共同假设，增强大脑 淋巴引流将为AD提供治疗益处。为了解决这一假设，我们建议刺激 Piezo1基因(Aim1)和化学(AIM2)激活的脑淋巴引流 它们在阿尔茨海默病的发生和发展中的作用。总而言之，这项工作的结果不仅将确定 PIEZO1作为AD的新靶点，也为增强脑淋巴循环提供了概念基础 引流是治疗各种神经系统疾病的一种新方法。

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.