Meningeal Lymphatic Dysfunction May Be Factor In Alzheimer’s

Meningeal lymphatic vessels in the brain, newly discovered in 2014, play an essential role in maintaining a healthy homeostasis in aging brains and could be a new target for treatment, new research from a team of neuroscientists and engineers at Virginia Tech and the University of Virginia indicates.

The work sheds fresh light on the underlying mechanisms of brain aging, along with associated neurological diseases.

“Our results showed that someday this method could be used as a potential treatment to help alleviate the effects not only of Alzheimer’s, but also other age-related cognitive ailments,”

said Virginia Tech’s Jennifer Munson, a study co-author and an assistant professor in the Department of Biomedical Engineering and Mechanics within the College of Engineering.

Meningeal Lymphatic Vessels

As pervasive as Alzheimer’s disease may be, one of its most recognizable symptoms — a pronounced decline in cognitive function — is not isolated to Alzheimer’s. Mild cognitive impairment and even dementia can be a normal part of aging and can carry serious implications for an older adult’s autonomy and quality of life.

Both Alzheimer’s and age-related dementia are notoriously difficult to treat, due in part to scientists’ lack of understanding about these diseases.

Researchers, led by Jonathan Kipnis, chair of neuroscience at the University of Virginia School of Medicine, found that meningeal lymphatic vessels drain fluid from the central nervous system into the cervical lymph nodes and dysfunction of that drainage aggravates cognitive decline as well as Alzheimer’s disease pathology.

brain discovery

Credit: University of Virginia Health System

Moreover, when the researchers treated healthy aged mice with a molecule that increased meningeal lymphatic vessel size and fluid flow within those vessels, the mice showed improved performance on learning and memory tasks.

“As you age, the fluid movement in your brain slows, sometimes to a pace that’s half of what it was when you were younger. We discovered that the proteins responsible for Alzheimer’s actually do get drained through these lymphatic vessels in the brain along with other cellular debris, so any decrease in flow is going to affect that protein build-up.”

said Munson.

VEGF-C Hydrogel

To see if the flow could be manipulated, Munson and study co-author Chase Cornelison engineered a hydrogel that contained a molecule known as vascular endothelial growth factor C or VEGF-C.

“Basically, this hydrogel diffuses VEGF-C through the skull and onto those lymphatic vessels in the brain, which causes them to swell. Together with our collaborators at UVA, we used MRI technology to show that as a result of this treatment, the bulk flow of fluid in the brain actually increased, and that seemed to have a positive effect on cognitive abilities,”

said Munson.

Virginia Tech's Jennifer Munson

Virginia Tech’s Jennifer Munson works with cell culture media in her lab.
Credit: Virginia Tech

Hydrogels, which are commonly used in research to deliver proteins or molecules to a specified site on the body, find frequent applications in tissue engineering, wound healing, and stem cell research.

“The hydrogel itself in this study isn’t novel, but the application is,”

said Munson.

Munson noted that older mice with normal, age-impaired cognitive abilities experienced the biggest gains in memory and learning from the treatment.

Decreased Flow Questions

Cornelison, a postdoctoral research associate in biomedical engineering at Virginia Tech, said he and Munson hope to use similar hydrogels in future studies as a noninvasive method to alter flow in the brain.

“We want to characterize the cellular response to these changes in flow,” he said. “We know that increased flow in these vessels appears to increase cognitive function, but we don’t know why. Why is slower flow a problem? Is it because you have decreased nutrient transport or increased waste accumulation? Outside of Alzheimer’s disease, we’re not really sure what could be in that fluid that’s causing just normal, age-related cognitive decline.”

Munson, who studies flow in the fluid and matrix-filled space surrounding cells known as interstitial space, thinks the answers to those questions might lie upstream from the brain’s major drainage pathways.

“Right now everyone is really focused on bulk flow in the brain, or the overall movement of flow in the brain,” said Munson. “But to really understand the mechanisms of why flow is linked to cognitive outcomes, we need to look at what’s happening around the neurons and astrocytes—all the cells that are in the brain.”

Because Munson’s lab works with interstitial fluid flow, she says her team already has the systems in place to take that next step.

Sandro Da Mesquita, Antoine Louveau, Andrea Vaccari, Igor Smirnov, R. Chase Cornelison, Kathryn M. Kingsmore, Christian Contarino, Suna Onengut-Gumuscu, Emily Farber, Daniel Raper, Kenneth E. Viar, Romie D. Powell, Wendy Baker, Nisha Dabhi, Robin Bai, Rui Cao, Song Hu, Stephen S. Rich, Jennifer M. Munson, M. Beatriz Lopes, Christopher C. Overall, Scott T. Acton & Jonathan Kipnis
Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease
Nature (2018)

Top Image: Obstructing lymphatic vessels (in green) in a mouse model of Alzheimer’s disease significantly increased the accumulation of harmful plaques in the brain. Credit: Kipnis lab