Summary: Researchers identified the missing exit portal: microscopic openings in the arachnoid membrane termed arachnoid fenestrations. Located within a specialized lymphatic network between the olfactory bulbs and the cribriform plate, these 2 to 12 micrometer openings allow CSF to pass directly into meningeal lymphatic vessels, traverse the nasal mucosa, and drain into deep cervical lymph nodes.
The team demonstrated that this specialized gateway is conserved in nonhuman primates (Macaca fascicularis) but undergoes dramatic structural regression during aging, leading to severe CSF stasis. Crucially, the researchers showed that intranasal administration of a VEGF-C viral vector stimulated lymphangiogenesis, fully restoring CSF clearance in aged mice without requiring invasive intracranial surgery.
Key Facts
- Microscopic Clearance Gateways: The study reveals that the arachnoid membrane is not a contiguous, impermeable barrier; it contains specialized, 2 to 12 micrometer openings (arachnoid fenestrations) concentrated near the cribriform plate that act as exit valves for CSF.
- Direct Functional Validation: Physical blockage of these micro-fenestrations using microspheres drastically reduced CSF drainage to cervical lymph nodes, proving that clearance relies on defined structural portals rather than passive diffusion around nerves.
- Evolutionary Conservation: Scanning electron microscopy (SEM) confirmed identical arachnoid fenestrations in nonhuman primates (cynomolgus monkeys), indicating that this drainage architecture is broadly conserved across mammals.
- Age-Related Structural Decay: In aged mice, arachnoid fenestrations decreased in both size and frequency, accompanied by marked regression of surrounding meningeal lymphatic vessels and reduced CSF flow.
- Non-Invasive Intranasal Rescue: Delivering a VEGF-C viral vector via a simple intranasal spray expanded the nasal and peri-olfactory lymphatic networks, successfully restoring CSF clearance in aged mice to youthful levels.
Source: Institute for Basic Science
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-ฮฒ, phosphorylated tau, and ฮฑ-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 โarachnoid fenestrationsโ, 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.
โBy 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,โ said HONG Seon Pyo, Research Fellow and co-first author of the study. โFinding similar structures in nonhuman primates suggests that this pathway may be broadly conserved among mammals.โ
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.
โUsing intranasal delivery of VEGF-C, we restored cerebrospinal fluid drainage in aged mice to levels comparable to young animals,โ said JIN Cheolhwa, co-first author. โWe 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.โ
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.
โThe arachnoid has traditionally been viewed as a protective barrier surrounding the brain,โ said Director KOH Gou Young, corresponding author of the study. โOur 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.โ
Key Questions Answered:
A: Neuroscience traditionally viewed the arachnoid membrane as a continuous, watertight seal insulating the central nervous system. This study demonstrates that the arachnoid is actually a dynamic interface featuring specialized 2 to 12 micrometer pores that act as regulated exit doors for CSF waste clearance.
A: The cribriform plate is the perforated bone separating the nasal cavity from the brain. The researchers found that the highest density of arachnoid fenestrations and specialized meningeal lymphatic vessels is concentrated right at this boundary, making it the primary highway for CSF exiting the skull into the lymphatic system.
A: While aging causes the physical fenestrations and bone openings to shrink, intranasal VEGF-C acts as a powerful growth factor that selectively expands the downstream mucosal and peri-olfactory lymphatic vessel networks. This increased vessel capacity acts like a higher-volume suction pump, pulling CSF through the remaining pores and completely restoring total clearance volume.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this psychopharmacology and eating disorder research news
Author:ย William Suh
Source:ย Institute for Basic Science
Contact:ย William Suh โ Institute for Basic Science
Image:ย The image is credited to Neuroscience News
Original Research:ย Open access.
โCSF clearance through arachnoid fenestrations to olfactory meningeal lymphaticsโ by Seon Pyo Hong, Cheolhwa Jin, Myung Jin Yang, Hokyung Jin, Jin-Hui Yoon, Du Ri Choi, Junho Jung, Chae Min Yuk, Salli Antila, Su Jin Seo, Leul A. Admasu, Jincheol Seo, Kyung Seob Lim, Won-Suk Chung, Kari Alitalo, Donald M. McDonald, Gou Young Koh.ย Cell
DOI:10.1016/j.cell.2026.06.035
Abstract
CSF clearance through arachnoid fenestrations to olfactory meningeal lymphatics
Meningeal (dural) lymphatics are essential for cerebrospinal fluid (CSF) clearance to cervical lymph nodes, yet the precise pathway is incompletely understood. Using a multifaceted approach in mice, we examined tracer dynamics and the CSF outflow pathway from the subarachnoid space (SAS) to the nasal mucosa and identified a discrete arachnoid region surrounding the olfactory bulbs with abundant fenestrations.
Similar arachnoid fenestrations were found in cynomolgus monkeys. Fluorescent tracers in the SAS passed through arachnoid fenestrations into dural lymphatics, which traversed the cribriform plate foramina, joined the nasal lymphatics, and drained to the cervical lymph nodes.
In aged mice, the known reduction in CSF outflow was accompanied by lymphatic atrophy in the olfactory dura and nasal mucosa and by fewer arachnoid fenestrations and smaller cribriform plate foramina. Importantly, the lymphatics and CSF clearance were restored to normal by intranasal delivery of vascular endothelial growth factor-C (VEGF-C), thereby documenting the reversibility of the aging-related impairment in CSF clearance.
