Effect of Brain Lymphatic Activation on Alzheimer's Disease Progression

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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.