The brain continuously produces metabolic waste that must be removed to maintain healthy function. Cerebrospinal fluid (CSF) plays a central role in this process by carrying away proteins such as amyloid-β, phosphorylated tau, and α-synuclein, which are linked to Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders when they accumulate abnormally.
Scientists have long known that much of this waste ultimately leaves the brain through lymphatic vessels and drains into lymph nodes in the neck. Yet one fundamental question has remained unanswered: How does cerebrospinal fluid cross the arachnoid membrane, a protective barrier separating the brain from the surrounding lymphatic system?
A research team led by Director KOH Gou Young at the Center for Vascular Research within the Institute for Basic Science (IBS), together with collaborators in Korea, Finland, and the United States, has now identified the missing anatomical gateway. The researchers discovered microscopic openings in the arachnoid membrane, which they named “arachnoid fenestrations”, that allow cerebrospinal fluid to pass directly into meningeal lymphatic vessels. The findings reveal the most detailed pathway yet for brain waste clearance and identify a drainage route that progressively deteriorates during aging but can be functionally restored in aged mice.
The team combined three-dimensional whole-mount imaging, genetically engineered reporter mice, tissue clearing, scanning electron microscopy (SEM), functional tracer experiments, and comparative studies in nonhuman primates. They identified a specialized lymphatic network located between the olfactory bulbs and the cribriform plate, the perforated bone separating the brain from the nasal cavity. Unlike other regions of the arachnoid membrane, this area contained numerous microscopic openings measuring approximately 2 to 12 micrometers in diameter.
Fluorescent tracers injected into the cerebrospinal fluid accumulated around these openings, crossed the arachnoid barrier, entered meningeal lymphatic vessels, traversed the cribriform plate, and continued through lymphatic vessels in the nasal mucosa before draining into cervical lymph nodes. Similar arachnoid fenestrations were also identified in cynomolgus monkeys, suggesting that this specialized drainage structure is conserved beyond mice.
“By combining three-dimensional imaging with cerebrospinal fluid tracer experiments, we identified microscopic openings in the arachnoid membrane that serve as functional gateways for CSF drainage,” said HONG Seon Pyo, Research Fellow and co-first author of the study. “Finding similar structures in nonhuman primates suggests that this pathway may be broadly conserved among mammals.”
To determine whether these openings were essential for CSF drainage, the researchers physically blocked them using microspheres too large to pass through the fenestrations. This dramatically reduced cerebrospinal fluid drainage to cervical lymph nodes, providing direct functional evidence that the fenestrations serve as critical exit portals for CSF. Together, the findings show that brain waste follows a defined lymphatic pathway rather than simply diffusing around olfactory nerves before entering the nasal lymphatic system.
The researchers next examined how this drainage system changes with age. Compared with young adult mice, aged mice exhibited widespread deterioration throughout the pathway. Lymphatic vessels surrounding the olfactory bulbs regressed markedly, while arachnoid fenestrations became both smaller and fewer in number. Openings within the central cribriform plate also narrowed substantially, and these structural changes coincided with a pronounced reduction in cerebrospinal fluid drainage.
Instead of delivering treatment by penetrating the meninges, the membrane that cover the brain, the team administered an adeno-associated viral vector expressing vascular endothelial growth factor-C (VEGF-C) through the nasal cavity. VEGF-C is a signaling molecule that promotes lymphatic vessel growth. This less invasive intranasal approach selectively expanded lymphatic vessels surrounding the olfactory bulbs and within the nasal mucosa. Although it did not restore the age-related loss of arachnoid fenestrations or enlargement of the cribriform plate openings, the expanded lymphatic network restored cerebrospinal fluid drainage in aged mice to levels comparable to those observed in young animals.
“Using intranasal delivery of VEGF-C, we restored cerebrospinal fluid drainage in aged mice to levels comparable to young animals,” said JIN Cheolhwa, co-first author. “We are now investigating whether this drainage pathway is disrupted in Alzheimer's and Parkinson's disease, and whether preserving its function could delay disease onset or progression.”
Impaired cerebrospinal fluid clearance has been increasingly linked to aging and neurodegenerative disorders. By identifying the anatomical gateway through which CSF enters the lymphatic system and demonstrating that this pathway can be functionally restored in aged mice, the study provides a new framework for understanding how brain waste clearance changes during aging.
“The arachnoid has traditionally been viewed as a protective barrier surrounding the brain,” said Director KOH Gou Young, corresponding author of the study. “Our findings show that it also contains specialized gateways that allow cerebrospinal fluid to enter the lymphatic system. Understanding how these gateways change with aging opens new opportunities for studying brain waste clearance and neurological disease.”
The findings were published in Cell .
Cell
Experimental study
Animals
CSF clearance through arachnoid fenestrations to olfactory meningeal lymphatics
21-Jul-2026