Lymphoid-like structures in the brain of a healthy person
Shiju Gan/Harvard University
Your brain may contain a hidden network of vessels that help it get rid of metabolic waste. If confirmed to be true in future studies, the discovery could transform our understanding of the brain and even reveal new therapies for conditions such as Alzheimer’s disease.
– If true, this is huge, says Per Kristian Eide at the University of Oslo, 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 flow into the lymphatic system, the body’s drainage and filtration system.
Most imaging studies have not detected lymphatic vessels in the brain, only in its protective outer layer. But now Chongzhao Ran of Harvard University and his colleagues may have discovered a hidden network of lymphatic-like brain vessels inside the brain that connect to the glymphatic system. “This is my most important discovery in 30 years,” says Ran. “It’s a scientist’s dream.”
Team member Shiju Gu, also at Harvard University, accidentally discovered the structures while looking for the protein beta-amyloid in brain slices from mice with an Alzheimer’s-like disease. Beta-amyloid helps neurons function, but it can form toxic clumps—a hallmark of Alzheimer’s—that can accumulate because of poor brain drainage.
When the researchers repeated the experiment on mice with and without an Alzheimer-like disease, they consistently found dozens of vessel-like structures in all the brain regions they sampled, including the 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 lymphatic vessels in the meninges—found in the outer protective layer—suggesting that they help drain waste via the lymphatic and lymphatic systems, Ran says.
Crucially, the researchers found the tube-like formations in brain samples from someone who died with Alzheimer’s disease. They have also found them in brain tissue from a person who died without the condition, according to Ran.
The team hypothesized that the structures were either a type of lymphatic vessel, lined by cells that contain or are coated with beta-amyloid, or a form of the protein that can develop into solid fibers that appear to contribute to Alzheimer’s disease but are sometimes also found in unaffected brains.
To find out, the researchers used protein markers that highlight lymphatic vessels on brain slices from mice. These consistently stained the tube-like structures, but less strongly than known lymphatics from the same animals. This led them to name the structures nanoscale lymphatic-like vessels, or NLVs, and conclude that they were not a form of beta-amyloid.
But Eide says the weak staining suggests that NLVs may not be lymphatic-like vessels, as these markers can also bind to non-lymphatic tissue. “This is a new type of structure we haven’t known about before – but it’s unclear, what exactly is this?”
One possibility is that the structures are an artefact caused by the imaging technique used, says Christopher Brown of the University of Southampton, UK. For example, if the tissue sample expanded unevenly, it could lead to vessel-like fractures, he says.
This may explain why previous brain imaging studies that used more reliable techniques, such as electron microscopy, have not reported NLVs before, says Brown. The team plans to use this in the next few weeks, says Gu, who adds that previous studies may have mistaken NLVs for axons, long projections from neurons that look like them.
“I’m 90 percent sure they are what we think,” Ran says, referring to another study by the team in which fluorescently labeled beta-amyloid in the brains of mice appeared to enter nearby NLVs, suggesting they transport waste fluid.
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 dilating the vessels improves the disposal of waste fluid.
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