The central nervous system (CNS) relies on specialized barriers and clearance routes to maintain a highly regulated environment. Proper management of metabolic waste and regulation of CSF dynamics are critical to preventing the accumulation of toxic byproducts. While dysfunctional cerebrospinal fluid (CSF) dynamics and impaired clearance have been associated with aging and Alzheimer’s disease (AD), the mechanisms that coordinate fluid production and drainage remain poorly understood. Understanding these mechanisms has the potential to open novel therapeutic avenues for neurodegenerative diseases by correcting disruptions in these sensitive, delicately balanced dynamics.
Dr. Kipnis’ team recently identified a novel mechanism where CSF production by the choroid plexus is directly linked to the drainage capacity of the meningeal lymphatic network. They demonstrated that mice produce less CSF as they age, which may reflect a progressively worsening drainage capacity. Conversely, when they enhanced drainage, they observed increased CSF production in both young and aged mice. Dr. Kipnis and his lab members hypothesize that this axis connecting CSF production and drainage is regulated by specialized signaling modalities, directly on choroid plexus epithelial cells. They also hypothesize that the age- and AD-associated decline in drainage triggers a reduction in CSF production, leading to fluid stagnation and the subsequent accumulation of amyloid beta.
In this project, they will test these hypotheses in AD mouse models using surgical, genetic, and pharmacologic approaches to manipulate lymphatic drainage and the activity of signaling molecules, to determine if they are the key controllers of CSF production. In doing so, they aim to confirm the mechanism tying CSF production to drainage and identify pharmacological targets.
