Scientists have made significant progress in restoring the brain’s waste disposal mechanism in older mice, paving the way for potential new treatments for Alzheimer’s and Parkinson’s diseases using already available medications.
Conditions such as Alzheimer’s and Parkinson’s can be characterized as “dirty brain” diseases, indicating that the brain has difficulty eliminating harmful waste. One major contributing factor is aging, which reduces the brain’s capability to expel toxic substances. Recent studies on mice reveal that it may be possible to counteract these age-related changes and enhance the brain’s waste removal abilities.
“Our findings indicate that by restoring the function of cervical lymph vessels, we can significantly improve the age-related decline in waste removal from the brain,” remarked Douglas Kelley, PhD, a professor of Mechanical Engineering at the University of Rochester’s Hajim School of Engineering and Applied Sciences. “Furthermore, this can be achieved using a clinically available drug, suggesting a new treatment approach.” Kelley is among the lead authors of the study published in the journal Nature Aging, alongside Maiken Nedergaard, MD, DMSc, co-director of the University’s Center for Translational Neuromedicine.
In 2012, Nedergaard and her team introduced the glymphatic system, which is the brain’s specialized waste removal mechanism that utilizes cerebrospinal fluid (CSF) to clear away excess proteins produced by energy-demanding neurons and other brain cells during regular function. This significant discovery has opened doors to potential new treatment methods for diseases linked to protein waste accumulation, like Alzheimer’s (which involves beta amyloid and tau proteins) and Parkinson’s (which includes alpha-synuclein). While healthy young brains efficiently clear these toxic proteins via the glymphatic system, this process slows down with age, contributing to the development of these disorders.
A network of small pumps removes waste from the brain
Once the CSF becomes filled with protein waste, it must travel from the skull to the lymphatic system and eventually to the kidneys, where it is eliminated along with other bodily waste. The new research utilizes advanced imaging and particle tracking to detail, for the first time, the journey taken by half of the contaminated CSF as it exits the brain via cervical lymph vessels in the neck.
The research team was able to not only measure CSF flow but also observe the rhythmic contractions of lymph vessels in the neck that assist in the removal of CSF from the brain. “Unlike the cardiovascular system, which relies on the heart as a single pump, lymphatic fluid transport involves a network of tiny pumps,” explained Kelley. These tiny pumps, known as lymphangions, incorporate valves to prevent backflow and connect to form lymph vessels.
The researchers discovered that, as the mice aged, the contractions of these pumps became less frequent and the valves began to malfunction, resulting in a 63 percent decrease in the rate at which contaminated CSF exited the brains of older mice compared to their younger counterparts.
A known drug stimulates the flow of brain-cleaning fluids
The team then aimed to see if they could reactivate the lymphangions and found that a drug called prostaglandin F2α, a compound similar to hormones used in medicine to induce labor, could aid smooth muscle contraction. Since lymphangions are covered in smooth muscle cells, the application of this drug to the cervical lymph vessels of older mice resulted in increased contraction frequency and enhanced flow of contaminated CSF from the brain, restoring efficiency levels similar to those in younger mice.
“These vessels are easily accessible near the skin’s surface, and we now understand their importance and how to boost their function,” said Kelley. “This strategy, potentially combined with other treatments, could pave the way for innovative therapies for these conditions.”
Other contributors to the study include first authors Ting Du, Aditya Raghunandan, and Humberto Mestre, along with Virginia Plá, Guojun Liu, Antonio Ladrón-de-Guevara, Evan Newbold, Paul Tobin, Daniel Gahn-Martinez, Saurav Pattanayak, Qinwen Huang, and Weiguo Peng from the University of Rochester. The study received support from various organizations, including 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 Medical Research Foundation, the Simons Foundation, the EU Joint Programme — Neurodegenerative Disease Research, the US Army Research Office, the National Center for Complementary and Integrative Health, and the BRAIN Initiative.
