In neurological inflammatory conditions like multiple sclerosis (MS), inflammatory immune cells may enter the brain through arachnoid cuff exit (ACE) points — newly discovered structures that normally seem to serve as a type of sewer system in the brain, helping to move out waste.
Figuring out exactly how immune cells and inflammatory signaling molecules move through ACE points — leading to inflammation in the brain — could lead to new therapeutic strategies for MS and other disorders, the researchers said in a study titled “Identification of direct connections between the dura and the brain,” which was published in Nature.
The brain is surrounded by a series of membranes called the meninges. It’s long been thought that these membranes basically wall off the brain from the rest of the body, protecting it from potentially harmful substances.
However, this new study shows there actually are gaps between the middle, or arachnoid layer of the meninges, and its outer layers, termed the dura mater, which the researchers described as the tough protective covering of the brain. The team found that some immune cells are able to move across these ACE points — and as such, they may be a sort of gateway for immune cells to pass through into the brain.
“The immune system uses molecules to communicate that cross from the brain into the dura mater,” Jonathan Kipnis, PhD, a professor at Washington University, in St. Louis, and a study author, said in a press release. “This crossing needs to be tightly regulated, otherwise detrimental effects on brain function can occur.”
Waste fluid moves from brain ‘much like how sewage leaves our homes’
The gaps between the layers of the meninges occur at places where blood vessels move across them, the researchers noted. Instead of forming a tight seal around these vessels, the arachnoid layer instead forms a looser ring more akin to a cuff — which led the team to name these structures arachnoid cuff exit points, or ACE points for short.
Through a series of imaging tests in mice and human volunteers, the researchers showed that fluid, molecules, and even some immune cells are able to move across ACE points. Based on how these substances flowed under normal conditions, the researchers think this probably serves as a way for waste to drain out of the brain.
Daniel Reich, MD, PhD, of the National Institute of Neurological Disorders and Stroke (NINDS) and a co-author of the study, likens this function of ACE points to how pipes carry sewage out of a house.
In this study, we asked the question of what happens once the ‘drain pipes’ leave the ‘house’ — in this case, the brain — and connect up with the city sewer system within the body.
“Waste fluid moves from the brain into the body much like how sewage leaves our homes,” Reich said.
“In this study, we asked the question of what happens once the ‘drain pipes’ leave the ‘house’ — in this case, the brain — and connect up with the city sewer system within the body,” Reich said.
If ACE points indeed serve as a way for the brain to discard waste, then they could have important implications for many neurological disorders, such as Alzheimer’s disease, that are marked by abnormal protein clumps in the brain.
“If your sink is clogged, you can remove water from the sink or fix the faucet, but ultimately you need to fix the drain,” Reich said.
“In the brain, clogs at ACE points may prevent waste from leaving. If we can find a way to clean these clogs, its possible we can protect the brain,” he said.
The work is a collaboration by scientists at Washington University and NINDS, part of the National Institutes of Health. It was funded by the NINDS Intramural Research Program, the National Institute on Aging, and the Cure Alzheimer’s Fund BEE Consortium.
More immune cells seen at ACE points in brain in MS mouse model
As part of the study, the researchers also examined what happens to ACE points in mice with experimental autoimmune encephalomyelitis (EAE) — a lab-induced inflammatory condition that’s commonly used to model MS.
The results showed that, under inflammatory conditions, there was a marked increase in the numbers of immune cells clustered around ACE points. The cells in the ACE points themselves also showed changes that appeared to make it easier for immune cells to pass through.
Based on these findings, the researchers speculated that ACE points may serve as an important entry point for inflammatory immune cells in disorders like MS.
If that’s true, it implies that preventing movement through ACE points may be a therapeutic strategy in neuroinflammatory disorders. The researchers stressed, however, that a lot more work is needed to understand the exact biological mechanisms involved.
“Unravelling the processes that govern the movement of cells and molecules through ACE points may provide therapeutic targets in neurological diseases,” the team wrote.
The scientists said the findings of this study provide “a conceptual framework to understand how the arachnoid barrier enables both separation and communication between meningeal layers.”
“We describe a new aspect of functional anatomy … and propose that ACE points are critical for … waste clearance and for neuroimmune communication in physiology and pathology [disease development],” they concluded.