A Review on The Glymphatic System and Meningeal Lymphatics

The maintenance of neuronal homeostasis within the central nervous system (CNS) requires the efficient removal of metabolic waste products and neurotoxic proteins. Historically, the CNS was considered devoid of a conventional lymphatic system, relying solely on passive diffusion for solute clearance. This paradigm shifted with the identification of the glymphatic system, a macro-scale waste clearance pathway dependent on glial cells, and the subsequent rediscovery of meningeal lymphatic vessels lining the dural sinuses. Cerebrospinal fluid (CSF) enters the brain parenchyma via peri-arterial spaces, exchanging with interstitial fluid (ISF) mediated by aquaporin-4 (AQP4) water channels localized on astrocytic endfeet. This convective flux facilitates the washout of soluble proteins, including amyloid-beta and tau, directing them toward the meningeal lymphatic network for drainage into deep cervical lymph nodes. Physiological factors, primarily sleep and arterial pulsation, critically regulate this fluid transport, while aging and traumatic injury impair its efficacy. Disruption of this dual-component clearance axis contributes significantly to the pathophysiology of neurodegenerative proteinopathies. Delineating the molecular and anatomical architecture of these systems offers novel therapeutic targets for conditions characterized by accumulation of misfolded proteins and metabolic stagnation.