Scientists restore brain’s waste disposal system

Alzheimer’s, Parkinson’s, and other neurological disorders can be thought of as “dirty” brain diseases, where the brain has trouble clearing out harmful waste. Aging is a key risk factor because as we age, our brain’s ability to clear out toxic buildup slows. However, new research in mice shows that it is possible to reverse the age-related effects and restore the brain’s waste removal process.

“This research shows that restoring cervical lymphatic vessel function can significantly rescue the slower clearance of waste from the brain associated with age,” said Douglas Kelley, Ph.D., professor of mechanical engineering in the Hajim School of Engineering and Applied Science at the University of Rochester.

“Furthermore, this was accomplished with a drug already in clinical use, offering a potential treatment strategy.” Kelley is one of the lead authors of the study, which appears in the journal Natural aging, with Maiken Nedergaard, MD, DMSc, co-director of the University’s Center for Translational Neuromedicine.

First described by Nedergaard and colleagues in 2012, the glymphatic system is a unique brain waste removal process that uses cerebrospinal fluid (CSF) to clear excess proteins generated by energy-hungry neurons and other brain cells during normal activity. This discovery has opened the door to potential new approaches to treat diseases commonly associated with the accumulation of protein waste in the brain, such as Alzheimer’s disease (beta-amyloid and tau) and Parkinson’s disease (alpha-synuclein).

In healthy, young brains, the glymphatic system efficiently removes these toxic proteins. However, with age, this system slows down, which promotes the onset of these diseases.

A network of tiny pumps removes waste from the brain

Once loaded with protein waste, CSF in the skull must travel to the lymphatic system and eventually to the kidneys, where it is processed along with the body’s other waste. The new research combines advanced imaging and particle tracking techniques to describe for the first time in detail the pathway through the cervical lymphatic vessels of the neck through which half of the dirty CSF exits the brain.

In addition to measuring CSF flow, the researchers were able to observe and record the beating of lymphatic vessels in the neck that help extract CSF from the brain.

“Unlike the cardiovascular system, which has one big pump, the heart, fluid in the lymphatic system is transported by a network of tiny pumps,” Kelley explains. These microscopic pumps, called lymphangions, have valves to prevent backflow and are connected together, one after the other, to form lymphatic vessels.

The researchers found that as the mice aged, the frequency of contractions decreased and the valves became defective. As a result, the rate at which dirty cerebrospinal fluid flowed out of the brains of older mice was 63 percent slower than that of younger animals.

Known drug boosts flow of brain-cleansing fluids

The team then looked at whether it was possible to reactivate the lymphangions and identified a drug called prostaglandin F2α, a hormone-like compound commonly used in medicine to induce labor and known to promote smooth muscle contraction. Lymphangions are lined with smooth muscle cells, and when the researchers applied the drug to the cervical lymph vessels of older mice, both the frequency of contractions and the flow of dirty CSF from the brain increased, returning to a level of effectiveness found in younger mice.

“These vessels are ideally located near the surface of the skin, we know they’re important, and now we know how to speed up their function,” Kelley said. “You can see how this approach, perhaps combined with other interventions, could provide the basis for future therapies for these diseases.”