Scan, Brain Of A Patient Affected By Alzheimers Disease,

Alzheimer’s Disease, Scan, Brain Of A Patient Affected By Alzheimers Disease, Axial Section. (Photo By BSIP/UIG via Getty Images)

Regulated clearance of substances out of the brain is critical to the healthy functioning of the nervous system and body, and the inability to clear abnormal molecules that clog brain cells is thought to contribute to declining brain health and neurodegenerative disease. Now, research demonstrates that a set of lymphatic vessels—thin-walled tubes that help rid the body of toxins, waste, and other unwanted materials—in the skull interacts with blood vessels to remove toxic waste products from the brain and has implications for cognition, aging, and neurological disorders, such as Alzheimer’s.

Waste management: body vs. brain

Humans are mostly made of water, and the insides of our bodies are soaked in a liquid that brings oxygen and nutrients to and carries waste products, such as metabolic trash, cellular debris, and toxic molecules, away from tissues and organs, which is critical to maintaining life. This fluid is composed of mostly interstitial fluid, which makes up around 20% of an adult human’s body weight, blood plasma, and lymphatic fluid (i.e. lymph)—the liquid that flows through the vessels of the lymphatic system.

Interstitial fluid circulates through a system of lymphatic vessels where it becomes lymph—filtered through lymph nodes that can trigger immune responses if foreign particles are detected—and, eventually, back to circulating blood plasma for eventual clearance from the body through the kidneys. These fluids are all relatively similar in makeup to permit water, ions, and small solutes to be continuously exchanged between them across the walls of blood and lymphatic vessels to maintain the health of the innumerable cells that comprise tissues and organs of the human body.

Although bathed in interstitial fluid and infused with blood vessels, the brain and spinal cord are not embedded with their own lymphatic vascular networks unlike the rest of the body. Uniquely, the central nervous system is protected by thick membranes made of connective tissue called the meninges that harbor cerebrospinal fluid—a transparent, colorless liquid with several critical functions including protecting the brain from physical impact and foreign, potentially harmful substances or particles.

Accordingly, cerebrospinal fluid enters the brain and spinal tissue and is coupled to a clearance mechanism for the removal of interstitial fluid from the nervous system through the glymphatic system (or paravascular circulation) that removes metabolic waste, cellular debris, and toxins from the brain. For many years, the glymphatic system—named in recognition for similarity to the lymphatic system and its dependence on brain cells called glia—seemed to answer to the long-standing question of how an organ as important and sensitive as the brain could operate without a lymphatic system.

Meningeal lymphatics (re)discovered

However, for all the attention focused on the brain in health and disease, the model for the brain’s fundamental clearance mechanisms was recently sent back to the drawing board with the rediscovery of the lymphatic system of the meninges in back to back papers by Louveau and Aspelund. First mentioned at the end of the 18th century by Paolo Mascagni, albeit with minimal acceptance let alone acknowledgment, it turns out that, in fact, there are conventional lymphatic vessels in the meninges and that this long-elusive tubing system hooks up with the glymphatic system to act as a drainage pathway for the brain and spinal cord.

In studies using several different approaches, meningeal lymphatic vessels were shown to be important for the clearance of macromolecules from cerebrospinal fluid in the meninges as well as from the interstitial fluid directly from brain tissue.

Alzheimer’s clogs neural plumbing

What’s more, recent research now demonstrates that the lymphatic vessels of the nervous system play a role in clearing Alzheimer’s disease-causing molecules and that disrupting the brain-plumbing organ severely impaired this process. Two studies examined the role of the meningeal lymphatic system in clearing different Alzheimer’s associated disease-causing substances—atypical forms of amyloid-β and tau—and whether this affected the brain’s health and cognitive abilities.

In one article, Da Mesquita and colleagues damaged the meningeal lymphatic system of mice by injecting a vessel-damaging drug into a large, cerebrospinal fluid-filled space in the meninges. These mice had cognitive defects in spatial orientation and fear memory, and the region in the brain linked to these behaviors—the hippocampus—was found to have a molecular signature that resembled those seen in neurodegenerative disorders.

In addition, Da Mesquita and colleagues damaged the meningeal lymphatic system of mice with Alzheimer’s disease by similarly injecting a vessel-damaging drug into the meninges. This damage to the meningeal lymphatics led to the accumulation of atypical amyloid-β in the meninges as well as accelerated the deposition of amyloid-β in brain tissue and associated cognitive deficits. To extend the relevance of these findings to humans, Da Mesquita and colleagues also showed that atypical amyloid-β had accumulated in the meninges of Alzheimer’s patients.

Whereas Patel and colleagues used mice that lacked a functional meningeal lymphatic system to examine the clearance of substances from the brain. They injected fluorescently labeled tau into healthy mice and ones with genetically ‘cut-out’ meningeal lymphatics, and, using a non-invasive imaging technique, Patel and colleagues quantified the glowing signal indicative of tau clearance from the brain. The results showed that mice lacking meningeal lymphatics cleared tau more slowly but were still able to clear tau, notwithstanding demonstrating impairment, indicating that the lymphatic pathway does not exclusively mediate tau clearance.

Together, these studies show that prolonged exposure to abnormal neurodegenerative disease-causing molecules impair the function of the meningeal lymphatic system in mice, likely because they are not cleared out of the brain properly. Additionally, impaired functioning of the meningeal lymphatic vessels as a result of aging can lead to accelerated accumulation of toxic Alzheimer’s associated molecules in brain tissue, aggravating neurodegeneration and worsening the disease.

Flushing out neurodegeneration

Characterization of the meningeal lymphatic system has major implications for understanding aging in the brain as well as treatments for neurodegenerative diseases. Furthermore, it is possible that meningeal lymphatics could contribute to autoimmune and inflammatory diseases of the nervous system due to their role in connecting the immune and nervous systems. As a result, it would be interesting to determine how the clearance of abnormal brain-clogging proteins is altered in the presence of significant Alzheimer’s disease as this will help us to understand the link between the brain’s drain and neurodegeneration.

For example, there is some evidence that, like mad cow disease, disruptive molecules can be released into the space surrounding cells, where they spread through different brain regions, enter unharmed cells, and seed disease. If neurodegenerative disease-causing molecules can be spread throughout the brain, understanding how this propagation occurs and how the brain clears these proteins and how this process fails in disease might help the development of effective therapies for neurodegenerative diseases.

This research raises new, interesting questions: does clearance of neurodegenerative disease-causing molecules through the lymphatic system change the impact of the disease? Is this process affected by aging? Most importantly, can this system be taken advantage of to flush out harmful molecules to the brain? There may be promise in strategies for local growth of lymphatic vessels to improve clearance by meningeal lymphatics, rebuild brain regulatory function, and lessen the accumulation of atypical amyloid-β and tau deposition.