As aging bodies decline, the brain loses the ability to cleanse itself of waste, a scenario that scientists think could be contributing to neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease. Researchers at Washington University School of Medicine in St. Louis report they have found a way around that problem by targeting the network of vessels that drain waste from the brain. Their study results indicated that rejuvenating those vessels improves memory in old mice.
The study could lay the groundwork for developing therapies for age-related cognitive decline that overcome the challenges faced by conventional treatments that struggle to pass through the blood-brain barrier to reach the brain.
“The physical blood-brain barrier hinders the efficacy of therapies for neurological disorders,” said Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology and a BJC Investigator at WashU Medicine. “By targeting a network of vessels outside of the brain that is critical for brain health, we see cognitive improvements in mice, opening a window to develop more powerful therapies to prevent or delay cognitive decline.”
Kipnis and colleagues reported on their results in Cell, in a paper titled, “Meningeal lymphatics-microglia axis regulates synaptic physiology,” in which they concluded that the study “… underscores the potential of enhancing meningeal lymphatic function to mitigate age-related synaptic and cognitive deficits.”
Kipnis is an expert in the field of neuroimmunology, which studies how the immune system affects the brain in health and disease. A decade ago, Kipnis’ lab discovered in mice and humans a network of vessels surrounding the brain—known as the meningeal lymphatics—that drains fluid and waste into the lymph nodes, where many immune system cells reside and monitor for signs of infection, disease, or injury. “Meningeal lymphatic vessels, located in the dura mater of the meninges, drain cerebrospinal fluid (CSF) together with its content of central nervous system (CNS)-derived waste primarily into deep cervical lymph nodes (dCLNs),” the authors wrote. Kipnis and colleagues also have previously shown that some investigational Alzheimer’s therapies are more effective in mice when paired with a treatment that improves drainage of fluid and debris from the brain.
Beginning at about age 50 years, as part of normal aging people start to experience a decline in brain fluid flow. The authors also pointed out that, “Since the discovery of meningeal lymphatic vessels, accumulating evidence from mouse models and humans has linked their dysfunction to various neurodegenerative conditions.” And while previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral changes, “… the neural mechanisms underlying these changes have remained elusive.”
For their newly reported study, Kipnis collaborated with Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology, to ask if enhancing the function of an aged drainage system can improve memory.
To test the memory of mice, the researchers placed two identical black rods in the cage for twenty minutes for old mice to explore. The next day, the mice received one of the black rods again and a new object, a silver rectangular prism. Mice that remember playing with the black rod will spend more time with the new object. But old mice spend a similar amount of time playing with both objects.
Study first author Kyungdeok Kim, PhD, a postdoctoral fellow in the Kipnis lab, then boosted the functioning of the lymphatic vessels in old mice with a treatment that stimulates vessel growth, enabling more waste to drain out of the brain. He found that, compared with older mice given no treatment, those older mice with rejuvenated lymphatic vessels spent more time with the new object, an indicator of improved memory. “We demonstrated that enhancing meningeal lymphatics can reverse aging-related memory deficits and restore decreased cortical inhibitory tone,” the authors wrote.
“A functioning lymphatic system is critical for brain health and memory,” said Kim. “Therapies that support the health of the body’s waste management system may have health benefits for a naturally aging brain.”
When the lymphatic system is so impaired that waste builds up in the brain, the burden of cleaning falls to the brain’s resident immune cells, called microglia. But this local cleaning crew fails to keep up and gets exhausted, Kipnis explained.
The new study found that the overwhelmed cells produce a distress signal, the immune protein interleukin 6 (IL-6), that acts on brain cells to promote cognitive decline in mice with damaged lymphatic vessels. Examining the brains of such mice the researchers found that neurons had an imbalance in the types of signals they receive from surrounding brain cells. In particular, neurons received fewer signals that function like noise-canceling headphones among the cacophony of neuron communications. This imbalance, caused by increased IL-6 levels in the brain, led to changes in how the brain is wired and affected proper brain function. “Our data suggest that the observed reduction in inhibitory inputs is mediated by an excess of IL-6, a proinflammatory cytokine associated with various neuropsychiatric and neurodegenerative conditions,” the team wrote.
In addition to improving memory in the aged mice, the lymphatic vessel-boosting treatment also caused levels of IL-6 to drop, restoring the noise-canceling system of the brain. “In addition, we observed reduced levels of Il6 (along with Tnfa) in VEGFC-treated aged mice,” the authors further noted. The findings point to the potential of improving the health of the brain’s lymphatic vessels to preserve or restore cognitive abilities.
Noting limitations of their study, the authors concluded: “Taken together, our findings highlight the essential role of meningeal lymphatics in maintaining the homeostasis of cortical networks … our study underscores the potential of enhancing meningeal lymphatic function to mitigate age-related synaptic and cognitive deficits.”
Kipnis said, “As we mark the 10th anniversary of our discovery of the brain’s lymphatic system, these new findings provide insight into the importance of this system for brain health. Targeting the more easily accessible lymphatic vessels that are located outside the brain may prove to be an exciting new frontier in the treatment of brain disorders. We may not be able to revive neurons, but we may be able to ensure their most optimal functioning through modulation of meningeal lymphatic vessels.”