Brain Entry and Exit Consortium: Glymphatic-Lymphatic Coupling in Alzheimer’s Disease

In Alzheimer’s disease (AD), toxic waste such as amyloid beta (Aβ) and tau accumulate and damage the brain, leading to cognitive decline and dementia. In most body organs, the lymphatic vessels in the tissue help to remove waste and also control the amount of fluid that is present. However, there are no lymphatic vessels inside of the brain, only on the membranes covering the brain (so-called “meningeal lymphatics”). Instead, the brain has a “glymphatic” system constructed in a specialized way to allow cerebrospinal fluid (CSF) to circulate and exchange with the fluids surrounding brain cells to help flush waste such as Aβ and tau out of the brain. Notably, the glymphatic system must connect to the meningeal lymphatics to effectively drain waste out of the brain. The recent discovery of the glymphatic and the meningeal lymphatic systems has led to heightened interest in understanding how brain waste drainage might be accelerated over the lifespan to avoid Alzheimer’s disease. Unfortunately, it has been technically challenging to study the waste removal processes and, most importantly, the important crosstalk between the glymphatic and lymphatic systems. Our laboratories have been developing and validating new imaging techniques and analysis tools based on computational fluid dynamics to visualize—in real time—how waste “solutes” and fluid pass through the two systems. The aim of this project is to implement these new technologies in a clinically relevant rat model of AD to characterize how the crosstalk between the glymphatic and lymphatic systems is affected by the disease. The results from this study will deliver novel tools and results to advance treatments for AD.