Brain Entry and Exit Consortium: A 3D In Vitro Neurovascular Human Brain Model With Meningeal Lymphatics for Elucidating Mechanisms Underlying Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia among older people. The blood-brain barrier (BBB) is a highly selective, permeable barrier that separates the brain from circulating blood. It is formed by brain endothelial cells and prevents harmful materials from the blood from entering the brain. The BBB also plays critical roles in removing toxic molecules, such as amyloid beta that causes AD, from the brain. The meningeal lymphatic vessels (meningeal lymphatics) are a network of conventional lymphatic vessels located parallel to the dural venous sinuses and middle meningeal arteries of the mammalian brain. Recently, it has been shown that the meningeal lymphatics have an important role in homeostasis of the brain by draining it of macromolecules, including amyloid beta. Although disruptions of the BBB and meningeal lymphatic vessels occur in various neurological disorders including AD, their contributions to the onset and progression of AD have not been fully elucidated. This is due, in part, to the lack of an effective model to capture the complex interactions between the various fluid compartments in the brain. Drawing upon our considerable experience in models of the BBB and neurovascular units, in combination with our collaborators in AD neurobiology, we propose to create new and more realistic models to capture the key interactions between the vascular, neural and meningeal compartments, and use these models to explore the process of disease and potentially identify new cures.