Brain’s Waste Exit Discovered... New Pathway for Dementia Treatment [Reading Science]

IBS Achieves World's First Identification of "Arachnoid Fenestrations"
Potential to Restore Impaired Brain Clearance Function Due to Aging

The "first gateway" through which brain waste products such as amyloid-beta, a key factor in dementia, are expelled from the brain has been identified for the first time by a Korean research team. The study also demonstrated that it may be possible to restore impaired brain waste clearance due to aging through gene therapy, opening up new avenues for research into treatments for degenerative brain diseases.

On July 22, the Ministry of Science and ICT announced that the research team led by Kyuyoung Koh, director of the Vascular Research Center at the Institute for Basic Science (IBS), had identified, for the first time in the world, a microscopic exit route called the "arachnoid fenestration" that allows cerebrospinal fluid to pass through the arachnoid mater, the membrane surrounding the brain, into lymphatic vessels. The research findings were published in the international journal "Cell."

3D structure, characteristics, and connections of olfactory bulb meningeal lymphatic vessels and nasal lymphatic vessels. (A) The olfactory bulb meningeal lymphatic vessels are well developed near the ethmoid bone plate, and lymphatic vessels are widely distributed inside the nose. (B) The olfactory bulb meningeal lymphatic vessels are directly connected to the lymphatic vessels of the olfactory mucosa inside the nose, with a very high density of lymphatic vessel development. Provided by the research team

The brain constantly generates waste products as a byproduct of its vigorous metabolic activity. These waste products are carried by cerebrospinal fluid and expelled from the brain. If this process does not function properly, neurotoxic proteins such as amyloid-beta can accumulate in the brain, increasing the risk of dementia and other degenerative brain diseases.

The IBS research team had previously revealed, in studies published in "Nature" in 2019 and 2024, that cerebrospinal fluid is expelled via meningeal lymphatic vessels and nasopharyngeal lymphatic vessels in the lower part of the brain to the cervical lymph nodes, with this pathway deteriorating with aging. Last year, they also identified an additional clearance pathway beneath the skin around the eyes and nose, and found that micro-mechanical stimulation could promote clearance via this route.

However, exactly how cerebrospinal fluid passes through the robust protective barrier of the arachnoid mater and enters the meningeal lymphatic vessels on the outer dura mater had long remained an unsolved puzzle.

Discovery of the "arachnoid fenestration," the starting point of brain cleaning

The research team used special mice with fluorescently labeled lymphatic vessels and advanced three-dimensional imaging techniques to observe that the lymphatic vessels in the anterior olfactory bulb are directly connected to the nasal lymphatic vessels, separated only by the thin ethmoid bone between the brain and the nasal cavity.

Further, through scanning electron microscopy and cerebrospinal fluid tracing experiments, they discovered tiny openings in the arachnoid mater and named them "arachnoid fenestrations."

Changes in olfactory bulb meningeal lymphatic vessels due to aging. (A~H) Compared to young mice, the olfactory bulb meningeal lymphatic vessels in aged mice were atrophied and degenerated, with lymphatic endothelial cells detaching. Provided by the research team

Cerebrospinal fluid carrying fluorescent markers passed through the arachnoid fenestrations and was absorbed by the meningeal lymphatic vessels. It then moved through the lymphatic vessels inside the nose and reached the cervical lymph nodes. The entire process of cerebrospinal fluid passing through the arachnoid mater and being expelled to the cervical lymph nodes was directly confirmed.

The researchers also identified similar arachnoid fenestrations in primates, suggesting that humans may possess a comparable waste clearance structure in the brain.

Kyuyoung Koh, Director of the IBS Vascular Research Center, stated, "This milestone achievement clearly elucidates the pathway of cerebrospinal fluid through the arachnoid mater—a problem that has persisted for some 250 years since the meningeal lymphatic vessels were first discovered. Our work lays the groundwork for a comprehensive understanding of the interconnected structures from the starting point of brain waste clearance to the cervical lymph nodes."

Aged clearance function restored to youthful levels

The research team also analyzed the impact of aging on the cerebrospinal fluid clearance pathway. In aged mice, the arachnoid fenestrations were narrowed and the surrounding meningeal lymphatic vessels were reduced. The passages through the ethmoid bone, traveled by both lymphatic vessels and olfactory nerves, were also narrowed, resulting in a marked decline in cerebrospinal fluid clearance function.

IBS Vascular Research Center Director Kyuyoung Koh (left), Research Leader Sunpyo Hong (center), and Researcher Cheolhwa Jin (PhD candidate, right). Courtesy of the Ministry of Science and ICT

The team administered the gene for vascular endothelial growth factor-C (VEGF-C), which promotes lymphatic vessel formation, to the nasal mucosa of aged mice. As a result, lymphatic vessels around the nasal cavity and olfactory bulb were regenerated, the clearance pathway widened, and the diminished cerebrospinal fluid clearance function was restored to a level comparable to that of young mice.

This suggests that delivering drugs intranasally—a relatively non-invasive approach—could improve brain waste clearance. However, as the research is still at the animal testing stage, further studies on human tissue and verification of safety and efficacy will be necessary before it can be applied to actual dementia patients.

Sunpyo Hong, the IBS research fellow who led the study, said, "By discovering the same arachnoid fenestration structure in primates, we have secured a crucial clue for clarifying the brain-cleaning mechanism in humans. We plan to expand our research to human tissues and develop therapeutic strategies applicable to various degenerative brain diseases."

This content was produced with the assistance of AI translation services.