There are about 170 billion cells in the brain, and as they go about their normal business, they produce a lot of waste. To stay healthy, the brain needs to flush out all that junk. But how exactly it does this has remained a mystery. Now, two teams of scientists have published three papers detailing the brain’s waste-disposal system. Their insights could help researchers better understand, treat, and perhaps prevent a wide range of brain disorders.
The papers, all published in the journal Nature, suggest that during sleep, slow electrical waves push fluid around cells from deep within the brain to its surface. There, a complex interface allows waste in the fluid to be absorbed into the bloodstream, which carries it to the liver and kidneys for removal from the body.
One of the waste products eliminated is amyloid, a substance that forms sticky plaques in the brains of patients with Alzheimer’s disease.
There is growing evidence that Alzheimer’s disease disrupts the brain’s waste-clearing system, said Jeffrey Ayliffe, who studies neurodegenerative diseases at the University of Washington but was not involved in the new research.
The new findings should help researchers understand exactly what the problem is and perhaps solve it, Iliff says.
“If we restore drainage, can we prevent Alzheimer’s disease?” he asks.
The new research comes more than a decade after Iliffe and Danish scientist Dr Maiken Nedergaard first suggested that clear fluids in and around the brain are part of a waste-cleaning system.
Scientists call it the glymphatic system, a reference to the body’s lymphatic system, which helps fight infections, maintain fluid levels, and filter out waste and abnormal cells.
Jonathan Kipnis of Washington University in St. Louis, author of two new papers, argues that both systems work like the plumbing in a house.
“You have water pipes and sewer pipes,” Kipnis says. “So the water comes in clean, and then you wash your hands and the dirty water comes out.”
But the lymphatic system uses a network of thin tubes that transport waste into the bloodstream. The brain doesn’t have such tubes.
So, Kipnis says, scientists have spent decades trying to answer a fundamental question: “How does a waste molecule from the middle of the brain get to the edge of the brain” and eventually get eliminated from the body?
Part of the answer came in 2012 and 2013, when Iliffe and Nedergaard began proposing the glymphatic system. They showed that in sleeping animals, cerebrospinal fluid begins to flow rapidly through the brain, flushing out waste.
But what was pushing the fluid? And how did it transport waste across the barrier that normally separates brain tissue from the bloodstream?
Kipnis and his team began studying how the brain works during sleep. As part of this effort, they measured the strength of the slow electrical wave that occurs during deep sleep in animals.
And they realized something: “By measuring the wave, we’re also measuring the flow of interstitial fluid,” the fluid found in the spaces around the cells, Kipnis says.
The waves turned out to act as a signal, synchronizing the activity of neurons and turning them into tiny pumps that push fluid to the surface of the brain, 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 from the Massachusetts Institute of Technology provided further evidence that slow electrical waves help clear waste from the brain.
The team used mice that were developing a form of Alzheimer’s disease. They exposed the mice to bursts of sound and light that occurred 40 times per second.
The stimulation caused the animals to produce brain waves that occurred at a uniform, slow frequency.
Tests showed that the waves increased the flow of clean cerebrospinal fluid into the brain and the outflow of dirty fluid from the brain. They also showed that the fluid carried amyloid, a substance that builds up in the brains of Alzheimer’s patients.
In a paper published a few weeks earlier, Kipnis showed how waste, including amyloid, appears to penetrate the protective membrane that normally insulates the brain.
Kipnis and his team focused on a vein that runs through this membrane.
“There’s a sleeve around the vein that’s never completely sealed,” he says. “That’s where the spinal fluid comes out” and carries waste into the body’s lymphatic system.
Taken together, the new research shows that keeping the brain’s waste-clearing system functioning requires two distinct steps: one to flush waste into the cerebrospinal fluid surrounding the brain, and one to move it into the lymphatic system and eventually out of the body.
“We described them separately,” says Iliff, “but biologically they are almost certainly related.” Iliff says many of the new findings in mice have yet to be confirmed in humans. “The anatomical differences between rodents and humans,” he says, “are quite significant.”
However, he says the findings are consistent with research into the causes of neurodegenerative diseases such as Alzheimer’s.
Researchers know that the brain’s system for clearing waste can be disrupted by age, injury and diseases that clog blood vessels in the brain.
“These are all risk factors for Alzheimer’s disease,” Iliff says.
Impaired waste removal may also be a factor in Parkinson’s disease, headaches and even depression, says Iliff. So finding ways to help the brain clean itself out – perhaps by inducing these slow electrical waves – could prevent a wide range of disorders.