Cerebrospinal fluid drainage from the brain into the body is necessary to remove metabolic waste from the brain. The flow declines with age, and evidence strongly suggests that this is an important contribution to the build up of protein aggregates and other waste that drive the onset and development of neurodegenerative conditions. Much of the focus is on the glymphatic system of vessels at the base of the brain, but because Alzheimer's disease starts in the olfactory bulb region of the brain, a few researchers have focused on drainage through openings in the cribriform plate stucture located behind the nose. Restoring passage of cerebrospinal fluid through the cribriform plate via surgical intervention is the task undertaken by Leucadia Therapeutics, for example. Here, researchers further explore that drainage path to find other potential blockages that occur between the olfactory bulb and cribriform plate, and that may also need to be dealt with.
Researchers discovered microscopic openings in the arachnoid membrane, which they named "arachnoid fenestrations", that allow cerebrospinal fluid to pass directly into meningeal lymphatic vessels. The findings reveal the most detailed pathway yet for brain waste clearance and identify a drainage route that progressively deteriorates during aging but can be functionally restored in aged mice. The researchers identified a specialized lymphatic network located between the olfactory bulbs and the cribriform plate, the perforated bone separating the brain from the nasal cavity. Unlike other regions of the arachnoid membrane, this area contained numerous microscopic openings measuring approximately 2 to 12 micrometers in diameter.
Fluorescent tracers injected into the cerebrospinal fluid accumulated around these openings, crossed the arachnoid barrier, entered meningeal lymphatic vessels, traversed the cribriform plate, and continued through lymphatic vessels in the nasal mucosa before draining into cervical lymph nodes. Similar arachnoid fenestrations were also identified in cynomolgus monkeys, suggesting that this specialized drainage structure is conserved beyond mice. To determine whether these openings were essential for CSF drainage, the researchers physically blocked them using microspheres too large to pass through the fenestrations. This dramatically reduced cerebrospinal fluid drainage to cervical lymph nodes, providing direct functional evidence that the fenestrations serve as critical exit portals for CSF.
Instead of delivering treatment by penetrating the meninges, the membrane that cover the brain, the team administered an adeno-associated viral vector expressing vascular endothelial growth factor-C (VEGF-C) through the nasal cavity. VEGF-C is a signaling molecule that promotes lymphatic vessel growth. This less invasive intranasal approach selectively expanded lymphatic vessels surrounding the olfactory bulbs and within the nasal mucosa. Although it did not restore the age-related loss of arachnoid fenestrations or enlargement of the cribriform plate openings, the expanded lymphatic network restored cerebrospinal fluid drainage in aged mice to levels comparable to those observed in young animals.
Link: https://www.eurekalert.org/news-releases/1137060
View the full article at FightAging
