Brain Entry and Exit Consortium: Meningeal Mast Cell Control of Cerebrospinal Fluid Dynamics in Homeostasis and Alzheimer’s Disease

The brain has evolved a distinct and complex system of barriers and clearance routes to ensure its proper functioning. Neurons in the brain have a very limited ability to repair themselves. Thus, barriers act to protect the brain from harmful external factors that might cause irreparable damage. Neurons are also highly metabolically active cells, generating a great deal of waste that must be cleared from the brain to prevent the buildup of detrimental byproducts or toxic proteins, and the brain’s clearance routes act to drain these fluids and molecules and prevent harm. The brain’s barriers and clearance routes must all function properly to maintain brain health during homeostasis, and dysfunction in these systems has been observed in many neurological diseases, including Alzheimer’s disease (AD). We have recently identified a novel structure in the meninges, the multilayered tissue surrounding the brain, that allows both the entry and exit of molecules and cells to and from the brain. These routes represent a direct link between the brain and the periphery. We propose that passage through these structures is controlled, in part, by a specialized immune cell type in the meninges called mast cells, which can close the structure and thus block the “gates” of the brain. We further propose that the unintended consequence of brain “gates” closure would result in the buildup of toxic proteins that contribute to AD. Therefore, by targeting the cells and molecules that control passage through these structures, we can prevent or reverse the buildup of toxic proteins in AD. Additionally, we will explore the relationships between these cells and structures in healthy and AD brains to determine how they might contribute to AD in patients.