Researchers find way to reopen brain’s aging “drain” with nasal drug delivery

South Korean researchers have identified for the first time a pathway that clears waste from the brain and declines with age, and successfully restored its function by administering a drug through the nose.

A research team led by Koh Gyu-young of the Vascular Research Center at the Institute for Basic Science (IBS) announced on the 3rd that it had identified microscopic openings in the arachnoid membrane surrounding the brain as a key gateway for cerebrospinal fluid (CSF) to enter the lymphatic system. The findings were published in the international journal Cell.

The brain produces waste products such as beta-amyloid and tau proteins after metabolic activity. If these substances accumulate in the brain, they can cause neurodegenerative diseases such as Alzheimer disease. The waste is known to leave the brain through the CSF and enter lymphatic vessels outside the brain, but how it passes through the arachnoid membrane surrounding the brain had remained a mystery.

In a mouse model, the researchers discovered microscopic openings 2 to 12 micrometers (μm) in diameter in the brain’s arachnoid membrane and named them “arachnoid fenestrations.” After injecting a fluorescent tracer into the CSF, the researchers clearly confirmed a pathway through which it exited through these openings and entered lymphatic vessels. Similar structures were also found in crab-eating macaques, suggesting that the mechanism may be common across mammals.

The study found that this clearance system deteriorated rapidly with age. Compared with young mice, older mice had fewer and smaller arachnoid fenestrations, while the surrounding lymphatic vessels had also atrophied, resulting in a marked reduction in CSF clearance.

To address the problem, the researchers administered vascular endothelial growth factor-C (VEGF-C), which promotes lymphatic vessel growth, into the nasal cavities of older mice. This noninvasive approach expanded the lymphatic vessels around the brain and restored CSF clearance to levels seen in young mice.

“This study opens new opportunities for research on brain waste clearance and neurologic diseases,” Koh said. “We are conducting follow-up studies to determine whether this clearance pathway is impaired in diseases such as Alzheimer disease and whether maintaining its function can slow disease progression.”