Columbia scientists have found that boosting the performance of a self-cleansing system in the brain helps flush amyloid and tau toxins from the brains of mice and improves the animals' cognition.
Their study also found that the brain cleansing system can be enhanced with drugs called PERK inhibitors, already in clinical trials for cancer, and suggests the drugs may also be beneficial for Alzheimer's and other neurodegenerative diseases.
"The glymphatic system-often called the brain's dishwasher-was only discovered about a decade ago and has captured the attention of many scientists," says Guang Yang, associate professor of anesthesiological sciences at Columbia University's Vagelos College of Physicians and Surgeons, who led the study.
Brain cleaning and Alzheimer's
Alzheimer's has been linked to a weak glymphatic system, so Yang and her team wanted to see how the two are connected, information that could yield new ways to treat or prevent the disease.
The researchers measured the performance of the brain's cleansing cycle by injecting a tracer into the cerebrospinal fluid of mice and using high-resolution microscopy to capture time-lapse images of the tracer in the glymphatic system.
Cleaning the brain. A green tracer fluid flows through the brain's glymphatic system, a recently discovered waste disposal system. The system moves waste along the outer edges of the brain's blood vessels (red). Images provided by Kai Chen.
In mice with Alzheimer's, the team found that the cleaning system becomes sluggish because channels that help drain metabolic waste from the brain are misplaced.
"It looks like the cells have enough of these AQP4 channels, but they're not in the right locations in the cells," Yang says. Normally, the channels are located at the endfeet of the astrocytes, star-shaped brain cells that control the glymphatic system. But in mice and people with Alzheimer's, the researchers found the channels distributed all around the astrocytes, which hindered waste removal from the cells.
The channels are misplaced in mice, the team found, because a protein called PERK is overactive. The researchers found that deleting the PERK gene or inhibiting it with a drug restored the channels to their proper location, increased amyloid and tau clearance, and improved the animals' cognitive performance.
A role for sleep?
Yang says there's still more to learn about the connection between the glymphatic system and Alzheimer's that could lead to new treatments. "This is just the starting point. We know PERK is important for controlling localization of the channel, but the details need to be worked out," she says.
Sleep may also help the glymphatic system clean the brain. Some studies suggest the glymphatic system is most active during sleep, and Alzheimer's is known to be associated with sleep disorders. "We're looking to see if PERK activity is linked to sleep, which might help explain how poor sleep could increase Alzheimer's pathology," Yang adds.
"Glymphatic impairment may be a common pathway in all neurodegenerative diseases, so our findings may also apply to other conditions."
References
More information
The study, "Selective removal of astrocytic PERK protects against glymphatic impairment and decreases toxic aggregation of β-amyloid and tau," was published May 19 in Neuron.
All authors (from Columbia unless noted): Kai Chen, Yosuke M. Morizawa, Tal Nuriel, Osama Al-Dalahmah, Zhongcong Xie (Massachusetts General Hospital and Harvard Medical School), and Guang Yang.
This work was supported by the U.S. National Institutes of Health (R01AG041274).
Guang Yang, PhD, is an associate professor in the Department of Anesthesiology at Columbia University Vagelos College of Physicians and Surgeons.
