Brain Waste Clearance Depends on the Nose, Study Finds; Technique Developed to Reverse Age-Related Brain Decline

South Korean researchers have identified for the first time the key pathway through which waste in the brain is cleared through the nose and demonstrated that drug administration can reverse age-related functional decline.

A research team led by Kyu-young Koh, a distinguished professor at the Graduate School of Medical Science and Engineering at the Korea Advanced Institute of Science and Technology (KAIST), identified in three dimensions the pathway through which cerebrospinal fluid drains through microscopic openings in the arachnoid membrane surrounding the olfactory nerves into the dural lymphatic vessels of the brain. The Chinese biotechnology outlet BioOn reported on the 31st that the findings were published in the international journal Cell on the 21st (local time).

Cerebrospinal fluid protects the brain from external impact and plays an important role in removing metabolic waste products such as amyloid beta and phosphorylated tau. Impairment of this drainage function can lead to cognitive decline and neurodegenerative diseases such as Alzheimer disease.

The research team tracked the precise drainage route of cerebrospinal fluid using whole-tissue clearing and 3-dimensional imaging techniques in a mouse model. The researchers confirmed that cerebrospinal fluid flows directly into the dural lymphatic vessels surrounding the brain through tiny openings in the arachnoid membrane surrounding bundles of olfactory nerves. The same pathway was found in macaque monkeys, which are primates, suggesting that it may also apply to humans.

According to the study, aged mice showed overall deterioration of the brain’s waste-clearance system, including atrophy of the dural lymphatic vessels and a reduction in the number of openings in the arachnoid membrane. This is cited as one of the major causes of age-related cognitive decline.

In particular, the research team administered vascular endothelial growth factor-C (VEGF-C) into the nasal cavities of aged mice using an adeno-associated virus (AAV) vector. The researchers found that the atrophied lymphatic function returned to normal levels and that cerebrospinal fluid drainage improved markedly. The findings demonstrated that age-related declines in brain function can be reversed.

The study is significant because it resolves a longstanding debate over the mechanism of brain waste removal and provides the first evidence that age-related brain dysfunction may be reversible. It is expected to provide an important starting point for developing new treatment strategies for intractable brain diseases such as Alzheimer disease.