Researchers at the University of Rochester and the University of Copenhagen have identified a previously unknown component of brain anatomy in mice and in humans that acts as both a protective barrier and platform from which immune cells monitor the brain for infection and inflammation.
Scientists in the labs of Maiken Nedergaard, PhD, co-director of the Center for Translational Neuromedicine at the University of Rochester and the University of Copenhagen, and Kjeld Møllgård, MD, a professor of neuroanatomy at the University of Copenhagen, suggest that the newly discovered meningeal layer, designated SLYM (subarachnoidal lymphatic-like membrane), might be implicated in diseases including multiple sclerosis, central nervous system infections, and Alzheimer’s disease.
“The discovery of a new anatomic structure that segregates and helps control the flow of cerebrospinal fluid (CSF) in and around the brain now provides us a much greater appreciation of the sophisticated role that CSF plays not only in transporting and removing waste from the brain, but also in supporting its immune defenses,” said Nedergaard. The researchers report on their studies in Science, in a paper titled, “A mesothelium divides the subarachnoid space into functional compartments,” in which they wrote, “The functional characterization of SLYM provides fundamental insights into brain immune barriers and fluid transport.”
Advances in neuro-imaging and molecular biology have only recently enabled scientists to study the living brain at a level of detail not previously achievable. Nedergaard and her colleagues have transformed our understanding of the fundamental mechanics of the human brain and made significant findings to the field of neuroscience, including detailing the many critical functions of previously overlooked cells in the brain called glia and the brain’s unique process of waste removal, which the lab named the glymphatic system.
“Emerging evidence supports the concept that CSF acts as a quasi-lymphatic system in the central nervous system,” the authors wrote. However, they noted, “Despite the efforts dedicated to studying CSF flow along the glymphatic-lymphatic path, it remains to be determined how CSF is transported within the large cavity of the subarachnoid space.”
The reported study focuses on the membranes that encase the brain, which create a barrier from the rest of the body, and keep it bathed in CSF. The traditional understanding of what is collectively called the meningeal layer, a barrier comprised of individual layers known as the dura, arachnoid, and pia matter. “In this study, we explored how CSF and immune cell trafficking are organized within the subarachnoid space surrounding the brains of mice and humans,” the authors wrote.
Their discovery and analysis of the SLYM layer indicated that the membrane further divides and separates this subarachnoid space below the arachnoid layer into two compartments. While much of the described research evaluated the function of SLYM in mice, the team also reported its presence in the adult human brain.
SLYM is a type of membrane called a mesothelium, which is known to line other organs in the body, including the lungs and heart. Mesothelia typically surround and protect organs and harbor immune cells. The idea that a similar membrane might exist in the central nervous system was a question first posed by first author Møllgård, whose research is focused on developmental neurobiology, and on the systems of barriers that protect the brain. Discovery of this new membrane then raised the question of “… whether SLYM constitutes an impermeable membrane that functionally compartmentalizes the subarachnoid space,” the investigators commented.
Their analyses showed that SLYM is very thin and delicate—thinner than the dura—and just one or a few cells in thickness. Using tracer molecules of different sizes, the researchers were able to show that the membrane forms a tight barrier, allowing only very small molecules to transit: it seems to separate “clean” and “dirty” CSF. The results of studies in mice showed that “SLYM divides the subarachnoid space into an upper superficial and a lower deep compartment for solutes ≥3 kDa. SLYM is therefore a barrier that limits the exchange of most peptides and proteins, such as amyloid-b and tau, between the upper and lower subarachnoid space compartments.”
This last observation hints at the likely role played by SLYM in the glymphatic system, which requires a controlled flow and exchange of CSF, allowing the influx of fresh CSF while flushing the toxic proteins associated with Alzheimer’s and other neurological diseases from the central nervous system. “The observation that SLYM is a barrier for CSF solutes that have a molecular weight larger than 3 kDa will require more detailed studies but indicates a need to redefine the concept of CNS barriers to include SLYM,” the team further noted.
The discoveries will help researchers more precisely understand the mechanics of the glymphatic system, which was the subject of a recent $13 million grant from the National Institutes of Health’s BRAIN Initiative to the Center for Translational Neuromedicine at the University of Rochester.
The team’s findings indicated that SLYM may also be of importance to the brain’s defenses. The central nervous system maintains its own native population of immune cells, and the membrane’s integrity prevents outside immune cells from entering. In addition, the SLYM appears to host its own population of central nervous system immune cells that use the SLYM for surveillance at the surface of the brain, allowing them to scan passing CSF for signs of infection. “The meningeal membranes are hosts to myeloid cells responsible for immune surveillance of the CNS, and SLYM, owing to its close association with the brain surfaces, is likely to play a prominent role in this surveillance,” the scientists suggested.
Discovery of SLYM opens the door for further study of its role in brain disease. The team noted that larger and more diverse concentrations of immune cells congregate on the membrane during inflammation and aging. When the membrane was ruptured during traumatic brain injury, the resulting disruption in the flow of CSF impaired the glymphatic system and allowed non-CNS immune cells to enter the brain. “Herein, we showed a large increase in the number and diversity of immune cells residing in SLYM in response to acute inflammation and natural aging,” they stated. “Physical rupture of SLYM could, by altering CSF flow patterns, explain the prolonged suppression of glymphatic flow after traumatic brain injury as well as the heightened post-traumatic risk of developing Alzheimer’s disease.”
These and similar observations suggest that diseases as diverse as multiple sclerosis, central nervous system infections, and Alzheimer’s might be triggered or worsened by abnormalities in SLYM function. The results also indicate that the delivery of drugs and gene therapeutics to the brain may be impacted by SLYM function, which will need to be considered as new generations of biologic therapies are developed.
