Researchers Identify 'Gateway' for Brain Waste Clearance, Opening New Avenues for Brain Disease Treatment

A South Korean research team has discovered "arachnoid fenestrations," hidden microscopic pores that drain waste from the brain, and successfully restored the waste clearance function, which declines with age, through gene therapy in animal experiments.

The research team led by Director Koh Gou-young of the Center for Vascular Research at the Institute for Basic Science (IBS) announced on July 22 that they had identified the key pathway through which cerebrospinal fluid (CSF), which cleanses brain waste, passes through the meninges surrounding the brain to be absorbed and drained into the meningeal lymphatic vessels. The findings were published in the scientific journal Cell.

"This study clearly elucidates the 'pathway of cerebrospinal fluid through the arachnoid,' which has been a long-standing challenge since the meningeal lymphatic vessels were first discovered about 250 years ago," said Director Koh. "This provides a foundation for an integrated understanding of the connection structure from the starting point of brain waste drainage to the cervical lymph nodes."

The brain, the most important organ in the human body, is surrounded by various protective structures, and waste is constantly produced during active metabolic processes within it.

This waste is carried out of the brain by cerebrospinal fluid. If the production and drainage of cerebrospinal fluid are not smooth, neurotoxic proteins such as amyloid-beta (Aβ) can accumulate in the brain, potentially leading to neurodegenerative diseases, including dementia.

The research team previously identified that cerebrospinal fluid is drained to the cervical lymph nodes through the meningeal lymphatic vessels at the base of the brain and the nasopharyngeal lymphatic network. They also found that this pathway degenerates with aging, and discovered new drainage pathways through lymphatic vessels under the facial skin, such as around the eyes and nose, as well as the fact that drainage can be promoted through minute mechanical stimulation, findings which were published in Nature.

However, the team pointed out that how cerebrospinal fluid passes through the "arachnoid," which acts as a tough protective barrier among the meninges surrounding the brain, to enter the meningeal lymphatic vessels in the outer dura mater layer had remained an unsolved mystery for a long time.

In this study, to identify the microscopic drainage pathways that are difficult to see with the naked eye, the researchers used special mice with fluorescently labeled lymphatic vessels and advanced 3D imaging technology. They discovered that the lymphatic vessels in the olfactory bulb, a neural structure that transmits olfactory signals in front of the brain, and the lymphatic vessels in the nasal cavity are directly connected to each other through microscopic pores across the cribriform plate.

Subsequently, through scanning electron microscopy (SEM) imaging analysis and tracer experiments using fluorescent substances in the cerebrospinal fluid, they confirmed that the cerebrospinal fluid exits the arachnoid through the microscopic pores connecting the lymphatic vessels of the olfactory bulb and the nasal cavity, and travels to the cervical lymph nodes.

The research team stated that this shows the microscopic pores connecting the lymphatic vessels of the olfactory bulb and the nasal cavity are the gateway for cerebrospinal fluid to exit the arachnoid, and they named these microscopic pores "arachnoid fenestrations."

The team also compared aged mice aged 85 to 100 weeks with young mice aged 8 to 10 weeks to determine the effect of aging on this drainage pathway.

In aged mice, not only were the arachnoid fenestrations narrowed and the surrounding meningeal lymphatic vessels reduced, but the passages in the cribriform plate through which lymphatic vessels and olfactory nerves pass were also narrowed, significantly reducing the cerebrospinal fluid drainage function.

However, when a gene that promotes lymphatic vessel formation (VEGF-C) was administered to the nasal mucosa of the aged mice, the regeneration of lymphatic vessels around the nasal cavity and olfactory bulb was promoted, the drainage pathway through the lymphatic vessels widened again, and the reduced cerebrospinal fluid drainage function was restored to the level of young mice.

The research team said this suggests a new strategic possibility for treating neurodegenerative diseases such as dementia through a non-invasive method of administering drugs into the nose.

"We have confirmed the same arachnoid fenestration structure in primates, securing a key clue to uncovering the brain cleaning mechanism in humans," said Hong Sun-pyo, a research fellow who is a co-first author and corresponding author of the paper. "We plan to expand our research to human tissue and develop new therapeutic strategies that can be applied to various neurodegenerative diseases."

(Photo: Provided by IBS, Yonhap News)
※ Please note: This article was translated by AI and may contain errors.