#147 - Does Sleep Really Clean Your Brain?

Matthew P. Walker (0:02)

Hi there, it's Matt here, and welcome back to the podcast. Today we are going to talk about the glymphatic system, the network that removes the metabolic waste the brain produces each day, and that appears to do much of its work while you sleep. It is one of the best detective stories in modern neuroscience, and it is still being written. But we begin 240 years ago with a man who was right, and with what it cost him to be right too early. In 1787, an Italian anatomist named Paolo Mascagni published the first great atlas of the human lymphatic system, the body's drainage, the fine mesh of vessels that carries waste out of living tissue. Mascagni had mapped it with a scalpel, a lamp, and extraordinary eyes, and in his lifetime, he was the world's foremost authority on the plumbing of the human body. And in among those pages, on the tough outer membrane that wraps the brain, Mascagni described lymphatic vessels. Now, his atlas was in Latin, and it was never translated into English. So for a long while, it simply went unread. But in 1875, a Swedish anatomist named Gustaf Retzius put the matter to rest. Mascagni, he suggested, had grown so enamored of the lymphatic system that he had started seeing lymph vessels even where they did not exist, in the brain, for instance. That was more or less the end of it. A handful of anatomists did report similar structures over the following century, and were similarly ignored. But the consensus had set, and the vessels on the surface of the brain stayed off the map for the next 140 years. Hold on to Mascagni. We will come back to him twice, because you cannot understand why he was dismissed until you understand the thing everybody knew for certain. The thing that made dismissing him the careful, rigorous, sensible choice. Everybody knew that other tissues and organs in your body produce waste. Your muscles, your liver, the skin on the back of your hand, all of them generate cellular detritus, and all of them have vessels to carry it away, clearing out the residue of the day's work.

Every tissue except the brain. We didn't think the brain had such a service crew for clean up. Which is strange given what the brain actually does.

Neurons burn fuel at a rate that would embarrass a Formula One engine. Your brain is about 2% of your body weight, and it takes around 20% of your energy. So picture the most expensive restaurant in the city. Michelin stars, tasting menus, the works, a kitchen running full tilt every night for 80 years, and no back door, no dumpster, no dishwasher. That was the brain according to the textbooks I trained on. The brain is privileged, we said. The brain is special. And once a thing has a name, it stops being a question. It stayed quiet for decades, sitting in plain sight inside every anatomy textbook in every medical library in the world. Then, a Danish neuroscientist went looking. Her name is Meiken Neddegard. And at the University of Rochester, she and her colleagues did something so simple, it is faintly embarrassing, nobody had done it sooner. They injected fluorescent tracer into the cerebrospinal fluid of living mice. Molecular dye, glow-in-the-dark confetti essentially. Then they looked down into the living brain and watched where the confetti went. Based on everything the textbook said, it should have drifted the way a drop of ink spreads through a still glass of water.

Slowly, aimlessly, wherever chance took it, but it did not. Instead, it traveled. Fluid was pouring into the brain along the outside of the arteries, running through sleeves wrapped around the blood vessels as they dived down into the tissue. It flushed through, it mixed with the fluid bathing the neurons, then it swept out along the veins and carried the waste with it. A river with tributaries and a current and a mouth at the sea. Which raises the obvious question and it is the one they asked next. Rivers need something to move them. So what was doing the pushing? The answer was a water channel called aquaporin-4, studded across the end feet of astrocytes, the star-shaped cells that clasp onto blood vessels throughout the brain.

Take the channel away and in theory you break the pump. So they bred mice without it. In those mice, clearance of waste from the brain fell by 70%.

Compared, that is, with littermates who had the channel and were otherwise identical. Then they ran it again with the one waste product my field worries about most, amyloid beta, the protein fragment that aggregates into the plaques found in the brains of people with Alzheimer's disease. In mice missing that single channel, amyloid clearance fell by 55% against the same comparison. So, the brain had not been excused from the economy of waste after all. It had simply concealed the plumbing where nobody thought to look. Not a separate system of dedicated vessels, which is what everybody had been hunting for and failing to find, but a system folded around the blood vessels the brain already had, using its own glial cells as the pipework. And Nadergaard gave it the name I used at the top of this episode, which is a small act of genius, glymphatic glial for the cells that run it, lymphatic for the job it does. It had been there the entire time. Somebody just had to inject the dye and watch. But the part of this that reaches out of the laboratory and takes hold of you personally, was still a year away.