For years, scientists thought the brain lacked a lymphatic system, raising questions about how fluid, macromolecules, and immune cells escape the organ. In 2015, two studies in mice provided evidence that the brain does in fact have a traditional lymphatic system in the outermost layer of the meninges—the coverings that protect the brain and help keep its shape—but scientists hadn’t yet figured out the exact exit route cerebrospinal fluid (CSF) and molecules take.
In a study published today (July 24) in Nature, researchers show that there is a hot spot of meningeal lymphatic vessels at the base of the rodent skull that is specialized to drain CSF and allow proteins and other large molecules to leave the brain.
“What they showed very nicely is that the system of meningeal lymphatics is the drainage system of the CSF of the central nervous system,” says Jonathan Kipnis, a neuroscientist at the University of Virginia who did not participate in the new study, but coauthored the first 2015 study. “We’re just scratching really the surface of understanding what these vessels are doing.”
“I’m actually quite relieved because when we published in 2015 . . . we got a lot of contrasting comments and some people were not convinced that the lymphatics really can be involved in cerebrospinal fluid drainage because there was a lot of literature telling otherwise,” Kari Alitalo of the University of Helsinki tells The Scientist. Alitalo coauthored the second 2015 paper describing the brain’s lymphatic system, but was not involved in the current study.
Upon seeing the evidence published by the teams of Kipnis and Alitalo, Gou Young Koh, a researcher at the Korea Advanced Institute of Science and Technology, wanted to clarify exactly how CSF was draining. He and his colleagues used transgenic mice to visualize the anatomy and morphology of the brain’s lymphatic system. They found that, in contrast to dorsal meningeal lymphatic vessels, basal vessels were in close proximity to the fluid-filled space surrounding the brain and had specialized valves and junctions that could allow them to both take up and transport CSF.
When the authors followed CSF drainage with magnetic resonance in rats or a small molecule tracker injected into mice, they saw the tracer was taken up by the basal meningeal vessels and then exited the brain through them. The researchers didn’t see any uptake by dorsal vessels. Finally, they confirmed results that had been shown previously—that aged mice have a reduced turnover and outflow of CSF—and showed that the basal meningeal lymphatic vessels in older mice increased in number, yet were enlarged and dysfunctional, which could explain the animals’ impaired drainage.