Photo courtesy of NIH via Flickr. Beta-Amyloid plaques and tau in the brain.
Silas Gemma ’26
Science & Environment Editor
Researchers are developing a new non-invasive strategy for mitigating the symptoms and progression of neurodegenerative diseases, according to Nature Communications. As Cell & Bioscience reported, scientists are currently investigating how to reduce an agglomeration of Alzheimer’s-associated proteins, toxins and cellular debris by enhancing the brain’s ability to clear waste.
As the article explained, structures called meningeal lymphatic vessels compose a critical transport system that allows the brain to filter out toxins for other peripheral structures to metabolize. The National Institutes of Health calls this lymphatic network the body’s “sewer system,” stressing its purpose as a waste disposal.
As Miao Wang and colleagues reported in Nature Communications, these lymphatic vessels are located within the meninges — protective layers of tissue and fluid that lie beneath the skull and spine. Wang’s team reported that these vessels were only discovered in 2015, sparking new research into their function and how they may be manipulated for therapeutic purposes.
Lymphatic vessels compose the many components of the lymphatic network, which the NIH described as a system that systemically transports toxins and immune cells to be filtered. Cell & Bioscience reported that immune cells such as T cells, B cells and neutrophils have been found in areas near the lymphatic vessels, highlighting the interconnectedness of the lymphatic and immune systems.
The NIH explained that structures called the lymph nodes filter the contents of these vessels, called lymph, before they are released into the bloodstream. According to NIH, these lymphatic vessels run parallel to blood vessels throughout the body, and the discovery of these vessels within the brain may demonstrate that the central nervous system is part of the broader lymphatic network throughout the body.
To modify treatments targeting the lymphatic system for Alzheimer’s, the pathology and symptomatology of Alzheimer’s must be understood. According to the Alzheimer’s Association, Alzheimer’s is a progressive neurodegenerative disease, meaning that it is a brain-attacking disease that worsens over time. Alzheimer’s is a cause of dementia, not a form of dementia, and it is seen most commonly in those 65 or older.
The NIH explained that the condensation of a protein called beta-amyloid into structures called plaques is a very common indicator of Alzheimer’s. However, these plaques may not always be seen in those with Alzheimer’s.
NIH also reported that neurofibrillary tangles — wrapped-up strands of a protein called tau that aggregate in the cell — are even more commonly associated with Alzheimer’s. These are germane to the disease’s pathophysiology and symptomatology, or how the disease presents itself symptomatically and in the brain, because they disrupt the ability of the neuron to transport essential proteins across its axon. The Alzheimer’s Association pointed out that these plaques and tangles are particularly important to consider because they are thought to disrupt signaling between neurons, leading to neuronal death.
The NIH added that atrophy of synaptic boutons —the endings of axons where interneuronal communication begins, as educational website Neuroscientifically Challenged explains — may play a significant role in the disease’s symptoms.
According to Cell & Bioscience, the meningeal lymphatic vessels are also essential for the egress and equilibration of cerebrospinal fluid and interstitial fluid, which both have primary functions of cushioning the brain and circulating substances according to NIH. These canal networks are relevant to Alzheimer’s disease, since the network that ISF courses through is essential for clearing tau, the protein comprising the neurofibrillary tangles seen in Alzheimer’s-afflicted neurons.
Researchers elaborated that the meningeal lymphatic vessels — particularly the endothelial cells that compose them — are of particular importance in neurodegenerative disease because they demonstrate a progressive loss of function as the brain ages.
Researchers further detailed a promising, although invasive, strategy to revamp the declining meningeal cells, which involves injecting a cellular growth-promoting substance directly into a cavity within the brainstem. However, they noted that this is often not practical for patients with dementia due to the progressive nature of the disease.
Researchers proposed a non-invasive strategy to reawaken dysfunctional lymphatic cells using targeted light. Specifically, their studies involving aged mice with Alzheimer’s disease – abbreviated as AD mice – have demonstrated that a localized application of near-infrared light can revitalize some of these lymphatic cells, prompting them to continue functioning as waste disposals.
These researchers used AD mice to test their hypotheses. They applied light of a specific wavelength transcranially, or across the skull, before observing differences in lymphatic structure and external behaviors. Control mice were placed in an environment with traditional indoor lighting. The experimental mice received the treatment for 10 minutes at a time, three times a week, for four weeks.
Various changes in drainage and lymphatic vessel structure were noted. By using a dye that fluoresces in the presence of cerebrospinal fluid — one of the fluids drained by the lymphatic vessels — the researchers could determine the rate and level of fluid efflux facilitated by the lymphatic vessels. Fluid efflux refers to the process of fluid being drained from the vessels in the brain.
This was taken as an indicator of lymphatic cell performance. The researchers measured the amount of CSF drained into the deep cervical lymph nodes, which BioMed Central explained are the next stop for some CSF after circulating through the meningeal lymphatic tracks.
Wang and colleagues noted that the mice who received the light treatment demonstrated greater drainage of CSF into the cervical lymph nodes than the control mice. They additionally reported enhanced performance of the mice during post-treatment cognitive tests compared to the pre-treatment results. Their performance on some cognitive tests resembled that of young mice.
One test used to measure cognitive change was the Morris water maze, which, according to Mouse Metabolic Phenotyping Centers, involves placing mice in a water-filled container with an obscured platform at which they can exit. Assuming the water is aversive to mice, this test can help determine spatial cognition by measuring the time it takes a mouse to find the platform.
Researchers reported that the light-treated AD mice tended to find the platform more quickly than untreated controls, possibly indicating restored spatial cognition.
Wang and colleagues additionally reported results of post-experiment neuroanatomical analyses. Particularly, they used dyes to measure the presence of essential proteins, such as a protein essential for interneuron communication and a protein crucial for keeping the neuron stable by strengthening microtubules, or protein polymers that provide structure to the neuron.
In mice that received the treatment, the amount of these proteins increased, suggesting enhanced communication and structural support. Additionally, these mice demonstrated more orderly dendritic orientations, as opposed to the tangled, disjointed configurations seen pre-treatment.
In brain areas such as the prefrontal cortex, the treated mice demonstrated less beta-amyloid deposition, decreased neuron damage and decreased response of microglia — which the University of California, Irvine describes as the central nervous system analog to macrophages found in the rest of the body, which are responsible for responding to injury or inflammation and cleaning up cellular byproducts.
Wang and colleagues reported an increase in the diameter of lymphatic vessels in the AD mice after light treatment, which may suggest an enhanced capacity to drain abnormal proteins and toxins.
Additionally, the researchers reported that the application of this light may enhance the function of diseased mitochondria in the meningeal lymphatic cells, promoting metabolic activity, energy production and cell growth. They suggested that mitochondrial restoration may lead to more efficient clearance of excess or aberrant proteins, possibly mitigating the symptoms and progression of age-related neurodegenerative disorders like Alzheimer’s.
The study also found that the proximity of the meningeal lymphatic cells to the skull is helpful for developing a localized and effective treatment, as the light does not have to travel deep into the brain.
The results from animal models suggest a possible future treatment for Alzheimer’s. They demonstrated that this novel, non-invasive treatment solely uses the manipulation of light to reinvigorate the brain’s pre-existing sewer system. It is now part of the rapidly growing repertoire of potential treatments for Alzheimer’s and related causes of dementia.