Scientists only recently discovered that the brain is not perfectly isolated from the rest of the body’s natural defense mechanisms and actually benefits from the immune system’s support. The glymphatic and meningeal lymphatic systems together monitor the brain for toxins and other unwanted byproducts that collect in cerebrospinal fluid, and provide an exit path for brain debris. In the brain, small openings called arachnoid cuff exit (ACE) points allow cerebrospinal fluid carrying waste to drain into an outer area rich in immune cells that act as sentinels and allow limited exchange of these cells and molecules back into the brain.

One of the most intriguing implications of this discovery is its potential connection to Alzheimer’s disease. Preliminary data suggests that ACE points become clogged with amyloid beta plaques, interfering with the removal of these harmful proteins and waste from the brain. The clogged ACE points also may prevent immune cells from accessing the brain to remove more amyloid beta or damaged cells.

This study provides an understanding of how the brain accommodates the immune surveillance and clearance of waste, offering new insights into neuroinflammatory conditions and overall brain health.

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The brain is the body’s control center, managing everything from thoughts and movement to essential functions like breathing and heart rate. Because of its importance, a series of barriers surround the brain to protect it. One function of these barriers is to isolate the brain from the rest of the body so that toxins or pathogens cannot access the protected space where the brain resides. However, the brain is not as isolated as once thought. Scientists have uncovered tiny structures known as arachnoid cuff exit (ACE) points, which facilitate the exchange of cerebrospinal fluid and immune cells between the brain and its outer protective layer, the dura mater. These ACE points play a vital role in maintaining brain health.

To fully comprehend the importance of this discovery, it is necessary to understand a few basics about how the brain is protected and the brain’s waste disposal system.

The brain is suspended in cerebrospinal fluid, which continuously washes over the brain, providing nutrients and removing waste. Layers of protective membranes, known as meninges, encase the brain and form compartments that serve different functions.

• The arachnoid barrier seals the brain and cerebrospinal fluid from the rest of the body.
• The dura mater, which sits directly outside the arachnoid barrier, contains the lymphatic vessels that drain waste fluid from the brain into the body’s lymphatic system.

However, this particular anatomy creates a problem. If the arachnoid barrier creates an impassable divide between the brain and the dura mater, how does the cerebrospinal fluid get to the dura mater to drain into the body’s lymphatic system?

“The lymphatic vessels are the sink of the brain. Eventually, the cerebrospinal fluid has to come into that sink,” Dr. Jonathan Kipnis explains. “But how it was happening was not known because the arachnoid barrier is supposed to prevent anything from getting through to the dura.”

To investigate how fluid from the brain was reaching the dura despite the presence of an apparent impenetrable barrier, Dr. Kipnis and his colleagues used advanced imaging techniques in both humans and mice to watch the path of cerebrospinal fluid from the brain to the dura. Large veins, known as bridging veins, pass through the arachnoid barrier as they carry blood from the brain to the dura. Small cuff-like openings form where the bridging veins exit the arachnoid barrier, allowing for the exchange of fluids between the brain and the dura. These points, coined arachnoid cuff exit, or ACE points, explain how the cerebrospinal fluid gains entry into the dura.

The researchers also found that ACE points play a role in immune surveillance. Before cerebrospinal fluid drains into the lymphatic system, the body’s immune cells, located in the dura, monitor the cerebrospinal fluid for signs of stress or the presence of pathogens. While ACE points most readily facilitate the movement of cerebrospinal fluid from the brain to the dura, it is possible for movement to happen in the reverse direction. If needed, immune cells from the dura can move through the ACE points towards the brain.

“In a normal healthy brain,” Dr. Kipnis explains, “immune cell trafficking is very, very restricted, maybe fully eliminated.” Cells sitting at the edges of ACE points release molecules that create a chemical stop sign to prevent immune cells from entering. However, when the brain needs assistance, the body’s immune cells are allowed entry into the protected space around the brain by removing the stop signal.

One of the most intriguing implications of this discovery is its potential connection to Alzheimer’s disease. Preliminary data indicates that amyloid plaques may clog ACE points, hampering the brain’s waste removal system. This blockage not only obstructs the clearance of harmful proteins but could also restrict immune cells from accessing the brain.

The discovery of ACE points redefines our understanding of brain anatomy and explains how the seemingly impenetrable arachnoid barrier manages the delicate balance between separation and communication. This discovery has significant implications for understanding brain waste clearance, immune surveillance, and the overall health of the brain.

Published in Nature

Jonathan Kipnis, Ph.D., Washington University School of Medicine in St. Louis

Identification of direct connections between the dura and the brain