Scientists investigating the "sewage system" of the brain search for mechanisms behind Alzheimer's

It's well-documented that genetics play a role in the risk of developing Alzheimer's disease (AD), a brain disorder that causes dementia through damage to brain cells and other changes in the brain. Age is a risk factor, too. Worldwide, an estimated 55 million people have the condition, and 500,000 new cases are diagnosed in the U.S. each year. Yet despite this knowledge, there hasn’t been as much progress as hoped to treat and reverse the devastating and ultimately fatal symptoms of cognitive decline caused by the disease. 

Currently, available treatments temporarily improve symptoms of memory loss and issues with thinking and reasoning. However, they don’t entirely stop the underlying decline and death of brain cells.

But two new studies published this week take a look at the brain’s so-called “sewage system,” uncovering more details about its mechanisms that could lead scientists to a new approach in treating Alzheimer’s. In the first study published in the journal Nature, scientists say they’ve discovered that brain cell activity during sleep is responsible for moving and propelling cerebrospinal fluid through and out of the brain. This mechanism essentially cleans the human brain of its debris, which contributes to the progression of Alzheimer’s.

“This question bothered us for a long time: how do you move the fluid through the dense tissue of the brain?” Jonathan Kipnis, PhD, co-author of the study and a BJC Investigator, told Salon, adding that the brain is unique because unlike other parts of the human body it doesn’t have “lymphatic vessels.”

Kipnis’s team came close to finding these so-called “pipes” to clean the sewage in the brain that existed in the brain’s borders in the dura mater, operating within the glymphatic system, which is driven by force. “What we're showing now is when the neurons are firing together and in synchrony, even though only very few neurons are firing —  because of the synchrony — you have big waves, and that force is what moves the flow through the brain tissue," he said.

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Brain cells are responsible for our thoughts, feelings, and physical movements. Together, they form an intricate network that is necessary for memory and problem-solving. However, in order to perform tasks our brain cells need fuel via nutrient consumption. In this process, waste, the so-called debris, is created. Researchers believe that the debris needs to be thrown out as any build-up of it can lead to neurodegenerative diseases like Alzheimer's.

This garbage disposal occurs during sleep, so to to investigate the force behind the cleaning, they looked at the brains of sleeping mice. In their experiment, the researchers identified that the neurons that drive the cleaning process are most active and efficient when the mice are sleeping. In fact, they moved via electrical pulses in synchronized, rhythmic waves signaling peak brain cell function, like Kipnis described. 

When researchers silenced specific brain regions, prohibiting neurons from engaging in those rhythmic waves, they found that the fresh cerebrospinal fluid could not flow through leaving behind trapped waste. 

“Suddenly, that brain region becomes a swamp,” he said. "The fluid is moving in it as efficiently as it would move if neurons were active.”

In a follow-up experiment, researchers were able to see how the fluid moves. First, cerebrospinal fluid, which surrounds and enter the brain, moving through it all while collecting waste. As it exits the brain, the contaminated fluid moves through a barrier before spilling into the outer tissue layer of the brain, underneath the skull.

“We saw that the movement of flow through the brain region was intensified,” he said, adding that one purpose of sleep is to “cleanse the brain. “And if we can enhance this cleansing process, perhaps it’s possible to sleep less and remain healthy.’

The researchers said not everyone can get eight hours of sleep, and that loss of sleep can have an impact on health — like dementia. Indeed, getting good sleep reduces the risk of dementia. Kipnis said genetics is indisputable when it comes to getting Alzheimer’s. But if anyone lives long enough, they increase their risk of getting the disease. The number of people with Alzheimer's doubles about every 5 years after the age of 65. 

In the second study, also published in Nature, researchers revealed a key mechanism in which amyloid proteins, which are part of the debris and a hallmark of Alzheimer’s, can be completely removed. Lead author of the study, Mitch Murdock, who is also a doctoral student at the Massachusetts Institute of Technology (MIT), told Salon that previous research suggested this happens while sleeping, “which suggests that there's something about neuronal rhythms and neuronal activity that activates the clearance pathway.” In their study, they tested their idea by relying on neuromodulatory stimulation in mice. 

“What we found is that when we turn on this sensory stimulation, there is an increase in the CSF movement into the brain,” Murdock said. “And this was associated with other cellular players that the field has shown are important for glymphatic clearance including recruiting those aquaporin water channels.”

Murdock said this study, and the others, emphasize the importance of behavioral interventions. 

“I think the takeaway is the importance of sleep,” Murdock said. “And this is consistent with many other studies showing how sleep and that healthy lifestyle including exercise, diet, social interactions, all promote brain health.”

Kipnis added both studies highlight the importance of “synchronized activity of neurons.” 

“It also could be that different waste will require different waves from different brain regions,” Kipnis said. “I’d I think they are all in agreement of the external forces and external things that really affect how the brain functions and how the brain maintains itself.”