Researchers have reversed the accumulation of waste products in the brains of ageing mice using a clinically approved drug that promotes waste removal and has the potential to treat neurological diseases.
Alzheimer’s diseaseParkinson’s and other neurological disorders are often considered “dirty brain” diseases, in which the brain struggles to remove harmful waste products. As we age, our risk of these diseases increases significantly because the brain’s ability to remove toxic buildup decreases. However, recent studies in mice have found that it may be possible to reverse these age-related changes and restore the brain’s waste removal process.
“This study shows that by restoring function to the cervical lymphatics, we can significantly reverse the slowdown in waste removal from the brain that occurs with aging,” said Douglas Kelly, PhD, professor of mechanical engineering at the Hajim School of Engineering and Applied Science at the University of Rochester. “Furthermore, this was achieved with a drug already in clinical use, thus providing a potential therapeutic strategy.” Dr. Kelly is one of the lead authors of the study, published in Nature Aging, along 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 the brain’s unique waste-cleaning process, which uses cerebrospinal fluid (CSF) to flush out excess proteins produced by neurons and other cells in the brain that use up a lot of energy during normal brain activity.
This discovery points the way to potential new approaches to treat diseases commonly associated with the accumulation of waste proteins in the brain, such as Alzheimer’s (beta-amyloid and tau) and Parkinson’s (alpha-synuclein). In healthy, young brains, the glymphatic system works well to flush 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 little pumps,” Kelly said. 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 these blood vessels are close to the surface of the skin and are important, 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.”
Reference: “Restoration of cervical lymphatic function in aging aids cerebrospinal fluid drainage” Ting Du, Aditya Raghunandan, Humberto Mestre, Virginia Plá, Guojun Liu, Antonio Ladrón-de-Guevara, Evan Newbold, Paul Tobin, Daniel Gahn-Martinez, Saurav Pattanayak, Qingwen Fan, Weiguo Peng, Maiken Nedergaard, Douglas H. Kelly, 15 August 2024, Nature Aging.
DOI: 10.1038/s43587-024-00691-3
Additional contributors to the study include first author Ting Du, Aditya Raghunandan and Humberto Mestre, and the University of Rochester’s Virginia Plá, Guojun Liu, Antonio Ladrón-de-Guevara, Evan Newbold, Paul Tobin, Daniel Gahn-Martinez, Saurav Pattanayak, Qinwen Huang and Weiguo Peng. This research was funded by the National Institute of Neurological Disorders and Stroke, the Lundbeck Foundation, the Novo Nordisk Foundation, the Human Frontier Science Program, the Miriam and Sheldon G. Adelson Foundation for Medical Research, the Simons Foundation, the EU Cooperative Research Program for Neurodegenerative Diseases, the U.S. Army Research Office, the National Center for Complementary and Integrative Health and the BRAIN Initiative.
