Scientists discover how to restore the brain's self-cleaning function

Alzheimer's, Parkinson's and other neurological disorders can be considered “dirty brain” diseases, in which the brain is unable to remove harmful waste products. Aging is a significant risk factor because as we get older, the brain's ability to remove toxic buildup slows. However, new research in mice demonstrates that it is possible to reverse the effects of aging and restore the brain's waste removal process.

“This study shows that restoring function to the cervical lymphatics could significantly reverse the age-related slowdown in waste clearance from the brain. Moreover, this has been achieved with a drug already in clinical use, offering a potential therapeutic strategy.”

Douglas Kelly, Ph.D., Professor of Mechanical Engineering, Hajim School of Engineering and Applied Science, University of Rochester

Kelly is one of the lead authors of the study, which appears in the journal Neurology. Natural aging, along with Maiken Nedergaard, MD, DMSc, co-director of the university's Center for Translational Neuromedicine.

The glymphatic system, first described by Nedergaard and colleagues in 2012, is the brain's unique waste-clearance process, which uses cerebrospinal fluid (CSF) to flush out excess proteins produced by energy-hungry neurons and other cells in the brain during normal activity. The discovery pointed the way to potential new approaches to treating diseases that are often associated with the accumulation of protein waste in the brain, such as Alzheimer's (beta-amyloid and tau) and Parkinson's (alpha-synuclein). In healthy, young brains, the glymphatic system is effective at flushing out these toxic proteins, but as we age, this system slows down, contributing to these diseases.

A network of tiny pumps moves waste products out of the brain

As the cerebrospinal fluid inside the skull fills with protein waste, it travels through the lymphatic system and eventually to the kidneys, where it is processed along with other waste products in the body. The new study combines advanced imaging and particle-tracking techniques to provide the first detailed description of the route that half of the dirty cerebrospinal fluid takes to drain from the brain through the cervical lymphatic ducts in the neck.

In addition to measuring the flow of cerebrospinal fluid, the researchers were able to observe and record the pulsation of lymphatic vessels in the neck that help drain cerebrospinal fluid from the brain. “Unlike the cardiovascular system, which has a large pump called the heart, the lymphatic system's fluids are transported by a network of tiny pumps,” Kelly says. These tiny pumps, called lymphatic vessels, have valves to prevent backflow and are connected together to form lymphatic canals.

The researchers found that as the mice aged, the contractions became less frequent and the valves became less functional, so that dirty cerebrospinal fluid leaked out of the brains of old mice 63 percent slower than in young mice.

Known drugs restart the flow of brain wash

The team then investigated whether they could revive the lymphatic vessels, identifying a drug called prostaglandin F2α, a hormone-like compound commonly used medically to induce labor and known to help smooth muscle contract. Lymphatic vessels are lined with smooth muscle cells, and when the researchers applied the drug to the cervical lymphatic vessels of older mice, both the frequency of contractions and the outflow of dirty CSF from the brain increased, returning them to the efficiency levels of younger mice.

“We know that these blood vessels are in a critical location near the surface of the skin, and now we know how to speed up their function,” Kelly said. “We see this approach, perhaps combined with other interventions, as potentially the basis for future treatments for these diseases.”