About 170 billion cells are in the brain, and as they go about their regular tasks, they produce waste — a lot of it. To stay healthy, the brain needs to wash away all that debris. But how exactly it does this has remained a mystery.
Now, two teams of scientists have published three papers that offer a detailed description of the brain's waste-removal system. Their insights could help researchers better understand, treat and perhaps prevent a broad range of brain disorders.
The papers, all published in the journal Nature, suggest that during sleep, slow electrical waves push the fluid around cells from deep in the brain to its surface. There, a sophisticated interface allows the waste products in that fluid to be absorbed into the bloodstream, which takes them to the liver and kidneys to be removed from the body.
One of the waste products carried away is amyloid, the substance that forms sticky plaques in the brains of patients with Alzheimer's disease.
There's growing evidence that in Alzheimer's disease, the brain's waste-removal system is impaired, says Jeffrey Iliff, who studies neurodegenerative diseases at the University of Washington but was not a part of the new studies.
The new findings should help researchers understand precisely where the problem is and perhaps fix it, Iliff says.
"If we restore drainage, can we prevent the development of Alzheimer's disease?" he asks.
A brief history of brainwashing
The new studies come more than a decade after Iliff and Dr. Maiken Nedergaard, a Danish scientist, first proposed that the clear fluids in and around the brain are part of a system to wash away waste products.
The scientists named it the glymphatic system, a nod to the body's lymphatic system, which helps fight infection, maintain fluid levels and filter out waste products and abnormal cells.
Both systems work like plumbing in a house, says Jonathan Kipnis of Washington University in St. Louis, an author of two of the new papers.
"You have the water pipes and the sewage pipes," Kipnis says. "So the water comes in clean, and then you wash your hands, and the dirty water goes out."
But the lymphatic system uses a network of thin tubes that transports waste to the bloodstream. The brain lacks these tubes.
So scientists have spent decades trying to answer a fundamental question, Kipnis says: "How does a waste molecule from the middle of the brain make it all the way out to the borders of the brain" and ultimately out of the body?
Part of the answer came in 2012 and 2013, when Iliff and Nedergaard began proposing the glymphatic system. They showed that in sleeping animals, cerebrospinal fluid begins to flow quickly through the brain, flushing out waste.
But what was pushing the fluid? And how was it transporting waste across the barrier that usually separates brain tissue from the bloodstream?
Waves that wash
Kipnis and his team began looking at what the brain was doing as it slept. As part of that effort, they measured the power of a slow electrical wave that appears during deep sleep in animals.
And they realized something: "By measuring the wave, we are also measuring the flow of interstitial fluid," the liquid found in the spaces around cells, Kipnis says.
It turned out that the waves were acting as a signal, synchronizing the activity of neurons and transforming them into tiny pumps that push fluid toward the brain's surface, the team reported in February in the journal Nature.
In a second paper published in the same issue of Nature, a team led by scientists at the Massachusetts Institute of Technology provided more evidence that slow electrical waves help clear out waste.
The team used mice that develop a form of Alzheimer's. They exposed these mice to bursts of sound and light that occurred 40 times a second.
The stimulation induced brain waves in the animals that occurred at the same, slow frequency.
Tests showed that the waves increased the flow of clean cerebrospinal fluid into the brain and the flow of dirty fluid out of the brain. They also showed that the fluid was carrying amyloid, the substance that builds up in the brains of Alzheimer's patients.
In a paper published a few weeks earlier, Kipnis had shown how waste, including amyloid, appeared to be crossing the protective membrane that usually isolates the brain.
Kipnis and his team focused on a vein that passes through this membrane.
"Around the vein, you have a sleeve, which is never fully sealed," he says. "That's where the [cerebrospinal fluid] is coming out" and transferring waste to the body's lymphatic system.
From mice to humans
Together, the new studies suggest that keeping the brain's waste-clearance system functioning requires two distinct steps: one to push waste into the cerebrospinal fluid that surrounds the brain, and another to move it into the lymphatic system and eventually out of the body.
"We've described them separately," Iliff says, "but from a biological perspective, they almost certainly are coupled."
Iliff says many of the new findings in mice still need to be confirmed in people.
"The anatomical differences between a rodent and a human," he says, "they're pretty substantial."
But he says the results are consistent with research on what leads to neurodegenerative disorders like Alzheimer's.
Researchers know that the brain's waste-clearance system can be impaired by age, injuries and diseases that clog blood vessels in the brain.
"All of these are risk factors for Alzheimer's disease," Iliff says.
Impaired waste removal may also be a factor in Parkinson's disease, headache and even depression, Iliff says. So finding ways to help the brain clean itself — perhaps by inducing those slow electrical waves — might prevent a wide array of disorders.
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