Summary: Researchers have identified a previously unrecognized exit route for cerebrospinal fluid (CSF): tiny openings in the arachnoid membrane, termed arachnoid fenestrations. These 2–12 micrometer pores are concentrated in a specialized lymphatic zone between the olfactory bulbs and the cribriform plate. CSF flows through these fenestrations into meningeal lymphatic vessels, passes through the nasal mucosa, and drains into deep cervical lymph nodes.
The team found that this gateway exists in nonhuman primates (Macaca fascicularis) but undergoes dramatic structural regression with age, producing substantial CSF stasis. Crucially, intranasal delivery of a VEGF-C viral vector stimulated local lymphangiogenesis and fully restored CSF clearance in aged mice without invasive intracranial procedures.
Key Facts
- Microscopic clearance gateways: The arachnoid membrane is not an impermeable sheet. In the region near the cribriform plate it contains numerous 2–12 μm fenestrations that serve as exit ports for CSF.
- Direct functional proof: Physically blocking these micro-fenestrations with microspheres that are too large to pass dramatically reduced CSF drainage to cervical lymph nodes, demonstrating their essential role.
- Conserved across species: Scanning electron microscopy revealed comparable arachnoid fenestrations in cynomolgus monkeys, indicating the pathway is conserved in mammals beyond mice.
- Age-related decline: In aged mice, fenestrations became fewer and smaller, meningeal lymphatic vessels regressed, and CSF flow decreased substantially.
- Non-invasive restoration: Intranasal administration of a viral vector expressing vascular endothelial growth factor-C (VEGF-C) expanded nasal and peri-olfactory lymphatic networks and restored CSF clearance in aged mice to youthful levels.
Source: Institute for Basic Science
Background: The brain continuously generates metabolic byproducts that must be removed to maintain function. CSF plays a central role in clearing proteins such as amyloid-β, phosphorylated tau, and α-synuclein. When these proteins accumulate abnormally they are implicated in neurodegenerative diseases including Alzheimer’s and Parkinson’s.
Although scientists have long known that much brain waste ultimately reaches lymphatic vessels and drains into cervical lymph nodes, the precise route by which CSF crosses the arachnoid membrane remained unclear. A multidisciplinary team led by Director Gou Young Koh at the Center for Vascular Research, Institute for Basic Science, has identified a specific anatomical gateway linking the subarachnoid space to meningeal and nasal lymphatics.
Using three-dimensional whole-mount imaging, genetically engineered reporter mice, tissue-clearing methods, scanning electron microscopy (SEM), functional tracer experiments, and comparative analysis in nonhuman primates, the researchers mapped a specialized lymphatic network located between the olfactory bulbs and the cribriform plate. Unlike other arachnoid regions, this area contains abundant microscopic openings approximately 2–12 μm in diameter.
Fluorescent tracers injected into the CSF accumulated at these fenestrations, crossed the arachnoid, entered meningeal lymphatic vessels, traversed cribriform plate foramina, and continued through lymphatic vessels in the nasal mucosa before reaching cervical lymph nodes. SEM confirmed similar fenestrations in cynomolgus monkeys, supporting evolutionary conservation of this drainage architecture.
To test function, the team blocked the arachnoid fenestrations with microspheres too large to fit through the pores. This blockade sharply reduced tracer transport to cervical lymph nodes, providing direct evidence that CSF clearance relies on these defined portals rather than passive diffusion around olfactory nerves.
Examining age-related changes, the authors found widespread deterioration across the pathway in aged mice: peri-olfactory dural lymphatics regressed, fenestrations reduced in size and number, and cribriform plate openings narrowed. These structural declines coincided with markedly reduced CSF outflow.
Seeking a minimally invasive intervention, the researchers administered an adeno-associated viral vector encoding VEGF-C via the nasal cavity. VEGF-C stimulates lymphatic growth; intranasal delivery selectively expanded lymphatic vessels around the olfactory bulbs and within the nasal mucosa. Although this treatment did not reverse the reduction in arachnoid fenestration number or enlarge the cribriform plate foramina, the expanded lymphatic network restored overall CSF clearance in aged mice to levels comparable to young animals.
“With intranasal VEGF-C we restored CSF drainage in aged mice to youthful levels,” said co-first author Cheolhwa Jin. The team is now exploring whether disruption of this pathway contributes to human neurodegenerative diseases and whether preserving or enhancing its function could delay disease onset or progression.
Impaired CSF clearance has been increasingly associated with aging and neurodegenerative disorders. By revealing the anatomical gateway through which CSF enters the lymphatic system and demonstrating functional reversibility in aged mice, this study provides a clearer framework for understanding how brain waste clearance changes with age and suggests new directions for therapeutic investigation.
Key Questions Answered
A: The arachnoid membrane was long viewed as a continuous, watertight barrier. This work shows it is a dynamic interface containing specialized 2–12 μm pores that act as regulated exit doors enabling CSF waste to enter meningeal lymphatics.
A: The cribriform plate separates the nasal cavity from the brain. The highest density of arachnoid fenestrations and specialized meningeal lymphatic vessels is concentrated at this boundary, making it a primary route for CSF to exit the skull into the lymphatic system.
A: Aging reduces pore size and number, but intranasal VEGF-C selectively expands downstream mucosal and peri-olfactory lymphatic networks. The increased vessel capacity effectively draws CSF through the remaining fenestrations, restoring total clearance.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by staff.
About this research news
Author: William Suh
Source: Institute for Basic Science
Contact: William Suh – Institute for Basic Science
Image: The image is credited to Neuroscience News
Original research: Open access. “CSF clearance through arachnoid fenestrations to olfactory meningeal lymphatics” by Seon Pyo Hong et al., published in Cell. DOI: 10.1016/j.cell.2026.06.035
Abstract
CSF clearance through arachnoid fenestrations to olfactory meningeal lymphatics
Meningeal lymphatics are critical for CSF clearance to cervical lymph nodes, but the exact outflow route has been incompletely defined. Using a combination of tracer dynamics, high-resolution imaging, and comparative studies in mice and nonhuman primates, researchers identified a discrete arachnoid region around the olfactory bulbs containing abundant fenestrations. Fluorescent tracers in the subarachnoid space passed through these openings into dural lymphatics, traversed cribriform plate foramina, joined nasal lymphatics, and drained to cervical lymph nodes. In aged mice, reduced CSF outflow was accompanied by lymphatic atrophy and fewer arachnoid fenestrations and smaller cribriform foramina. Intranasal delivery of VEGF-C restored lymphatic networks and CSF clearance, documenting reversibility of the aging-related impairment in CSF outflow.