Lymphatic structures in the brain of a healthy person
Shiju Gan/Harvard University
Your brain may contain a hidden network of blood vessels that help it dispose of metabolic waste. If proven true in future studies, the discovery could change our understanding of the brain and even reveal new therapies for conditions such as Alzheimer’s disease.
“If it’s true, it’s huge,” he says For Kristian Eide at the University of Oslo, Norway, who was not involved in the research. “It would represent a paradigm shift in our understanding of all neurodegenerative diseases, but also conditions such as stroke and traumatic brain injury, and our normal brain function.”
The brain cleans itself by releasing metabolic waste into the glymphatic system, a network of channels surrounding the brain’s blood vessels that feed into the lymphatic system, the body’s drainage and filtration system.
Most imaging studies have not seen lymphatic vessels in the brain, only in its protective outer layer. but now Chongzhao Ran at Harvard University and his colleagues may have discovered a hidden network of cerebral lymphatic vessels inside the brain that connects to the glymphatic system. “This is my most significant discovery in the last 30 years,” says Ran. “It’s a scientist’s dream.
Team member Shiju Gualso at Harvard University, spotted the structures by chance while looking for the beta-amyloid protein in brain slices from mice with Alzheimer’s disease. Beta-amyloid helps neuron function, but it can form toxic clumps—the hallmark of Alzheimer’s disease—that can build up due to poor brain outflow.
When the researchers repeated the experiment in mice with and without Alzheimer’s disease, they consistently found dozens of vessel-like structures in all the brain regions they sampled, including the cerebral cortex, which is involved in thinking and problem solving; the hippocampus, which helps us form memories; and the hypothalamus, which controls sleep and body temperature.
The structures appeared to wrap around the brain’s blood vessels and meningeal lymphatic vessels—found in the outer protective layer—suggesting they help drain waste through the glymphatic and lymphatic systems, Ran says.
Crucially, the researchers found tube-like structures in brain samples from someone who had died of Alzheimer’s disease. According to Ran, they were also found in the brain tissue of a person who died without the disease.
The team hypothesized that the structures were either a kind of lymphatic vessel, lined by cells that contain or are coated with beta-amyloid, or a form of protein that can develop into tough fibers that appear to contribute to Alzheimer’s disease, but are it also sometimes occurs in unaffected brains.
To find out, the researchers applied protein markers that highlight lymphatic vessels to brain slices from mice. These consistently stained tube-like structures, although less strongly than known lymphatic vessels from the same animals. This led them to name the structures nanoscale lymphatic vessel, or NLV, and concluded that it was not a form of beta-amyloid.
But Eide says the weak staining suggests that NLVs may not be lymphatic vessels, because these markers can also bind to non-lymphatic tissue. “This is a new kind of structure that we didn’t know about before – but it’s not clear what it actually is?”
One possibility is that the structures are an artifact caused by the imaging technique used, he says Christopher Brown at the University of Southampton in Great Britain. For example, once a tissue sample expands, it could lead to vessel-like fractures, he says.
This could explain why previous brain imaging studies that used more reliable techniques, such as electron microscopy, did not report NLV earlier, Brown says. The team plans to use this in the next few weeks, says Gu, who adds that earlier studies may have mistaken NLVs for axons, the long projections from neurons that look similar.
“I’m 90 percent sure they are what we think they are,” Ran says, referring to another study by the team where fluorescently labeled beta-amyloid in mouse brains appeared to enter nearby NLVs, suggesting they transport waste fluids.
If confirmed by other research groups, the findings could help our understanding of Alzheimer’s disease and other conditions associated with misfolded proteins, such as Parkinson’s disease. It could even lead to drugs that treat such conditions, says Brown, for example, if dilation of blood vessels improves waste fluid disposal.
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