How a New Drug is Helping the Aging Brain Stay Clean and Sharp

Brain Stay Clean and Sharp

Researchers have successfully reversed age-related brain waste accumulation in mice by utilizing a clinically approved drug, potentially paving the way for new treatments for neurological disorders.

Neurological conditions such as Alzheimer’s and Parkinson’s are often categorized as “dirty brain” diseases, wherein the brain struggles to expel harmful waste.

Aging dramatically heightens the risk of these disorders as the brain’s capacity to clear toxic buildup diminishes over time.

However, recent studies in mice indicate that it might be possible to counteract these aging-related changes and rejuvenate the brain’s waste-clearing mechanisms.

“This study demonstrates that restoring cervical lymph vessel function can significantly enhance the brain’s slower waste removal processes associated with aging,” stated Douglas Kelley, PhD, a professor at the University of Rochester’s Hajim School of Engineering and Applied Sciences.

“Additionally, this was achieved using a drug already approved for clinical use, offering a promising therapeutic strategy.” Kelley, a lead author of the study published in Nature Aging, collaborated with Maiken Nedergaard, MD, DMSc, co-director of the University’s Center for Translational Neuromedicine.

First identified by Nedergaard and her team in 2012, the glymphatic system is the brain’s specialized waste clearance process, employing cerebrospinal fluid (CSF) to remove surplus proteins produced by the brain’s energy-intensive neurons and other cells during routine activities.

This groundbreaking discovery suggested potential new methods for treating diseases linked to the accumulation of protein waste in the brain, such as Alzheimer’s (with beta-amyloid and tau) and Parkinson’s (with alpha-synuclein). In youthful and healthy brains, the glymphatic system efficiently flushes out these toxic proteins. However, as aging occurs, the system’s efficacy diminishes, setting the stage for these debilitating diseases.

A network of minuscule pumps draws waste from the brain

Once burdened with protein waste, the CSF in the skull must navigate toward the lymphatic system and eventually reach the kidneys for processing alongside other bodily waste.

The new research employs advanced imaging and particle tracking techniques to intricately map the route through cervical lymph vessels in the neck, through which a significant portion of contaminated CSF exits the brain.

In addition to measuring CSF flow, researchers were able to observe and document the pulsing of lymph vessels in the neck, which assists in drawing CSF out of the brain.

“Unlike the cardiovascular system, which relies on a single large pump—the heart—the lymphatic system utilizes a network of tiny pumps,” explained Kelley.

These microscopic pumps, known as lymphangions, are equipped with valves to prevent backflow and are linked sequentially to form lymph vessels.

The research revealed that as mice aged, the frequency of these contractions decreased, and the valves failed, leading to a 63 percent reduction in the speed of waste-laden CSF leaving the brains of older mice compared to younger ones.

Established drug revives brain-cleansing fluid flow

The research team then explored whether they could rejuvenate the lymphangions, identifying a drug called prostaglandin F2α—a hormone-like compound commonly used to induce labor and known for its role in aiding smooth muscle contraction.

Lymphangions are lined with smooth muscle cells, and when the drug was applied to the cervical lymph vessels in older mice, both the frequency of contractions and the flow of waste-laden CSF from the brain increased, returning to levels observed in younger mice.

“These vessels are conveniently located near the skin’s surface, their importance is clear, and we now understand how to accelerate their function,” Kelley noted. “This approach, potentially in combination with other interventions, could form the foundation of future therapies for these diseases.”

Reference

Restoration of cervical lymphatic vessel function in aging rescues cerebrospinal fluid drainage, by Ting Du, Aditya Raghunandan, Humberto Mestre, Virginia Plá, Guojun Liu, Antonio Ladrón-de-Guevara, Evan Newbold, Paul Tobin, Daniel Gahn-Martinez, Saurav Pattanayak, Qinwen Huang, Weiguo Peng, Maiken Nedergaard, and Douglas H. Kelley, published on 15 August 2024, in Nature Aging.

Additional contributors to the study include first authors Ting Du, Aditya Raghunandan, and Humberto Mestre, as well as 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 research was supported 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 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.

Brain Stay Clean and Sharp