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Meningeal lymphocytic dysfunction may be factor in Alzheimer's



Meningeal lymphatics in the brain, rediscovered in 2014, play a vital role in maintaining a healthy homeostasis in aging brains and could be a new treatment target for new research from a team of neuroscientists and engineers at the Virginia Tech and the University of Virginia.

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

"Our results showed that this method could someday be used as a potential treatment to alleviate the effects not only of Alzheimer's disease but also of other age-related cognitive disorders," said Jennifer Munson of Virginia Tech, co-author Assistant Professor at the Department of Biomedical Engineering and Mechanics at the College of Science Engineering

Meningeal Lymphatics

As far as Alzheimer's is concerned, one of the most prominent symptoms ̵

1; a pronoun decline in cognitive function – is not isolated to Alzheimer's. Mild cognitive impairment and even dementia can be a normal part of aging and have serious consequences for the autonomy and quality of life of older adults.

Alzheimer's and age-related dementia are known to be difficult to treat, due in part to a lack of understanding about these diseases.

Researchers, led by Jonathan Kipnis, Department of Neuroscience at the University of Virginia's Department of Medicine, found that meningeal lymphatics drain fluid from the central nervous system into the cervical lymph nodes and their malfunctioning drainage worsens cognitive decline as well as Alzheimer's disease pathology ,

  Brain Discovery

Credit: University of Virginia Health System

In addition, the researchers treated healthy mice aged with a molecule that increased meningeal lymph vessel size and fluid flow. Within these vessels, the mice showed improved performance in learning and memory tasks.

"As you get older, the fluid movement in your brain slows down, sometimes to a tempo that's half of what it was when you were younger." We discovered that the proteins responsible for Alzheimer's are responsible, in fact, be drained through these lymphatic vessels in the brain along with other cell debris, so any decrease in the flow will affect this protein buildup. "

Munson said.

VEGF-C Hydrogel

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

Hydrogel diffuses VEGF-C through the skull and into these lymphatic vessels in the brain, causing them to swell. Together with our staff at the UVA, we have demonstrated with MRI technology that as a result of this treatment, fluid flow in the brain actually increased, which had a positive effect on cognitive ability, "Munson

 Jennifer Munson of Virginia Tech

Jennifer Munson of Virginia Tech works in her laboratory with cell culture media
Credit: Virginia Tech

Hydrogels that are commonly used in research to make proteins or molecules into one Specific protein transport side to the body, finding frequent applications in tissue engineering, wound healing and stem cell research.

"The hydrogel itself in this study is not new, but the application is," Munson said [1965] [1965] See: Munson found that older mice with normal, age-related cognitive abilities had the largest gains in memory and from the treatment

Diminished Flows

Cornellison, a biomedical postdoctoral researcher The Virginia Tech researcher said he and Munson hope to use similar hydrogels as a noninvasive method in future studies to alter the flow in the brain.

"We want to characterize the cellular response to these changes in the flow," he said. "We know that increased flow in these vessels seems to enhance cognitive function, but we do not know why, why is slow flow a problem? Is it because you have reduced the nutrient transport or accumulation of waste outside Alzheimer's? We are not really sure what could be in this fluid, which causes only normal, age-related cognitive decline. "

Munson, who investigates the flow in the cell and cell-filled space known as Interstitial Space The answers to these questions may be upstream of the main brain drainage pathways.

"Right now, everyone is really focusing on the mass flow in the brain or the entire flow of the brain," Munson said. "But to understand the mechanisms of why flow is associated with cognitive outcomes, we need to investigate what's happening around the neurons and astrocytes – all the cells in the brain."

Because Munson's lab works on interstitial fluid flow, she says her team already has the systems to take the 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 Aging and Alzheimer's Disease
Nature (2018)

Picture above: Lymphatic vessels clogging (green) in a mouse model of Alzheimer's disease significantly increased the accumulation of harmful plaques in the brain. Credit: Kipnis Laboratory


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