Research by scientists at the University of Virginia (UVA) and Virginia Tech suggests that boosting the flow of fluid and macromolecules through a series of recently discovered lymphatic channels in the brain may offer a promising approach to prevent or at least hold back cognitive decline associated with aging or dementias such as Alzheimer’s disease. Studies headed by Jonathan Kipnis, M.D., chair of neuroscience at the UVA School of Medicine, showed that treating aging mice with a hydrogel that carries vascular endothelial growth factor (VEGF) C increased the flow and drainage of macromolecules from the cerebrospinal fluid through these meningeal lymphatic vessels, boosting learning and memory performance. Conversely, disrupting meningeal lymphatic vessels in transgenic mouse models of Alzheimer’s disease promoted deposits of amyloid-β deposits in the brain.

“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,” explains Jennifer Munson, Ph.D., assistant professor at Virginia Tech College of Engineering’s department of biomedical engineering and mechanics. “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.” Dr. Munson is co-author of the team’s published paper in Nature, which is titled, “Functional aspects of meningeal lymphatics in aging and Alzheimer’s disease.”

The brain has traditionally been viewed as an immunoprivileged organ that, when healthy, has “limited interactions with the immune system,” the authors wrote. Immune system cells are found primarily within the spaces between the meninges, the protective layers that cover the brain. It has also been thought that brain tissue doesn’t contain the same type of lymphatic vascular network that is found in other body tissues. As a result, the brain removes cellular debris and toxic molecules via alternative phagocytic and transcellular transport mechanisms that traverse the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier.

The UVA and Virginia Tech team, together along with other researchers, recently identified and characterized a system of lymphatic vessels within the brain meninges. The discovery of this fluid and macromolecule transport byway system is making researchers look more closely at how molecules are perfused through the central nervous system, and how waste is cleared. What isn’t yet understood is the exact role of the vessels in CNS function and disease. It’s also not known whether –  like lymphatic vessels in peripheral tissues –  these meningeal lymphatic vessels might start to function less efficiently as a result of aging, or whether, and if so how, they may be involved in clearing proteins, such as amyloid-β that forms toxic deposits up in the brains of Alzheimer’s disease patients.

Using different pharmacological, surgical, and genetic approaches the team first showed that disrupting or blocking the meningeal lymphatic vessels effectively slowed perfusion of CSF into the brain tissues of experimental mice, and drainage of interstitial fluid (ISF) back out into the cervical lymph nodes. In normal, young adult mice disruption of the meningeal lymphatic vessels was associated with impairments in the spatial learning and memory, and was also linked with “changes in gene sets associated with neurodegenerative diseases, such as Huntington’s, Parkinson’s and Alzheimer’s disease,” the team noted. They suggested that their results support the notion that “the observed effect is a result of dysfunctional meningeal lymphatic drainage and not an artifact of the ablation method …”

The risk of developing neurological disorders such as Alzheimer’s disease increases as we age; aging is also associated with poorer CSF and ISF recirculation within the brain. Coupling this fact with observations that aging is associated with dysfunction in the more comprehensively studied peripheral lymphatic vessels, led the authors to hypothesize that age-related deterioration of the meningeal lymphatic vessels may somehow underpin cognitive decline.

They first showed that that aging mice demonstrated both poorer perfusion of CSF macromolecules in the brain, and decreased drainage into the cervical lymph nodes. The aged mice also had fewer and narrower meningeal lymphatic vessels. This age-related meningeal lymphatic vessel narrowing could be reversed. Meningeal lymphatic vessel diameter and function were both increased in aged mice that were treated using a transcranially delivered hydrogel-encapsulated VEGF-C. The VEGF-C-treated animals in parallel demonstrated increased fluid drainage and enhanced brain perfusion of CSF macromolecules via the meningeal lymphatic vessels. “Basically, this hydrogel diffuses VEGF-C through the skull and onto those lymphatic vessels in the brain, which causes them to swell,” says Dr. Munson. “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.”

In a separate set of experiments aged animals treated using a viral vector-based VEGF-C gene construct also demonstrated increased lymphatic vessel diameter and drainage. Significantly, the VEGF-C gene therapy (mVEGF-C) was associated with improved learning and memory. These cognitive benefits weren’t evident if the meningeal lymphatic vessels in mVEGF-C-treated animals were blocked, however, demonstrating that “the beneficial effect of mVEGF-C treatment on cognitive behavior was through improved drainage of meningeal lymphatic vessels,” the authors wrote.

Given the results thus far, the team reasoned that altering meningeal lymphatic function might also have an effect on behavior and pathology of Alzheimer’s disease in mouse models. They found that disrupting meningeal lymphatic vessels led to a build-up of amyloid-β aggregates in the meninges and increased amyloid-β plaque load in the hippocampi. And when the researchers examined post-mortem brains of Alzheimer’s disease patients, they also found “prominent meningeal amyloid-β deposition, similar to that found in the mouse models of Alzheimer’s disease after meningeal lymphatic ablation.”

“Taken together, the present findings highlight the importance of meningeal lymphatic drainage in brain physiology,” the authors wrote. “Meningeal lymphatic dysfunction in young–adult mice results in impaired brain perfusion by CSF and in learning and memory deficits. Aged mice demonstrated significant disruption of meningeal lymphatic function, which may underlie some of the aspects of age-associated cognitive decline. Augmentation of meningeal lymphatic drainage in aged mice can ultimately facilitate the clearance of CSF and ISF macromolecules from the brain, resulting in improved cognitive function.”

The authors say it will be important to find out whether age-related changes in meningeal lymphatic drainage might affect the effectiveness of antibody-based and other treatments for Alzheimer’s disease. They also suggest that modulating meningeal lymphatic function in older people might help to prevent or delay age-related neurological disorders, such as Alzheimer’s disease, that are characterized by abnormal protein accumulation. “Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases,” they concluded.

“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,” comments Dr. Munson.

The researchers also aim to use hydrogels as a noninvasive method to alter brain flow. “We want to characterize the cellular response to these changes in flow,” says study co-author Chase Cornelison, Ph.D., a research associate in biomedical engineering at Virginia Tech. “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.”

And it may not be the brain’s major drainage pathways that hold the answer, Dr. Munson believes. “Right now everyone is really focused on bulk flow in the brain or the overall movement of flow in the brain … 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.”

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