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Scientists Uncover Connection Between Alzheimer’s and Immunity

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September is World Alzheimer’s Month, and unfortunately we need Alzheimer’s research more than ever.

According to the Alzheimer’s Association, more than 5.7 million Americans are currently living with Alzheimer’s, and that number is expected to more than double by 2050. While mortality rates for other diseases—including the number one cause of death, heart disease—have decreased, deaths from Alzheimer’s rose 123% between 2000 and 2015.

Alzheimer's disease is the 6th leading cause of death in the United States, and it is the only disease in the top 10 causes of death that cannot be prevented, cured or even slowed.

Researchers are working to change that, and there have been a number of Alzheimer’s related breakthroughs in the last year, including a study at Johns Hopkins Medicine connecting pH levels in brain cells to Alzheimer’s and a discovery by researchers at the Cleveland Clinic Lerner Research Institute that depleting the BACE1 enzyme in mice reverses the formation of amyloid plaques.

One of the most promising studies, from researchers at the University of Virginia School of Medicine, has found a strong connection between the immune system and cognitive decline, both from Alzheimer’s and the normal aging process.

Lymphatic Vessels in the Brain

Lymphatic vessels, which run next to blood vessels, collect and remove waste, which is then filtered through the lymph nodes and returned to the bloodstream.

The fact that the brain, like most of the body’s other organs, uses a lymphatic system to remove dead cells and other waste, is a recent discovery. Until very recently, scientists believed there were no lymphatic vessels inside the skull, but in 2015, mouse studies found evidence that the brain does have a lymphatic system located in the dura, a thick membrane that surrounds the brain and spinal cord.

That finding was confirmed in primate studies, and in 2017, researchers at the U.S. National Institute of Neurological Disorders and Stroke located the lymphatic vessels in the human brain.

Just as the other organs in the body use lymphatic vessels to cleanse and maintain their health, so does the brain. As the lymphatic vessels connecting the brain and the immune system degrade over time, the brain’s ability to function is compromised.

Researchers found that by improving the function of those vessels in aged mice, those mice showed dramatic improvement in their memory and learning ability.

The Alzheimer’s Connection

Using mouse models, researchers at the University of Virginia’s Department of Neuroscience and Center for Brain Immunology and Glia, developed a method to improve the flow of waste from the brain to the lymph nodes in older mice. After the procedure, the lymphatic vessels became larger and more efficient at draining waste, which resulted in an immediate and marked improvement on the mice’s ability to learn and remember.

By taking the opposite approach—obstructing the lymphatic vessels in mice—researchers showed that lymphatic vessel blockage causes an increase in the accumulation of amyloid plaques in the brain, one of the hallmarks of Alzheimer’s. Formed when beta-amyloid proteins clump together into a sticky mass, amyloid plaques disrupt cell functions and interfere with brain synapses.

Essentially, by blocking the function of the brain’s lymphatic system, researchers were able to mimic the appearance of Alzheimer’s in mice. The next step, which is already under way, is to develop a drug that improves the performance of the lymphatic vessels in people.

Boosting Immunity in the Brain

A separate mouse study by researchers at UCLA Health has found that boosting levels of the TREM2 protein, which makes the brain’s immune cells more effective at fighting disease and protecting brain cells, could help treat people with Alzheimer’s.

Mutations in the TREM2 gene are known to increase the risk of developing Alzheimer’s disease, and now scientists think that TREM2’s function is to help the brain fight the formation of amyloid plaques and other symptoms of Alzheimer’s.

To test the theory, researchers at the Semel Institute for Neuroscience and Human Behavior at UCLA and the Geffen School produced mice with elevated levels of TREM2 and bred them with mice engineered to develop amyloid plaques and other Alzheimer’s symptoms.

The mice bred to have both higher levels of TREM2 and the propensity to display features of Alzheimer’s developed fewer amyloid plaques, exhibited less inflammation, and showed improved ability to remove cell waste. Those mice also performed significantly better on memory tests.

It has not yet been proven whether boosting TREM2 will work in humans, but researchers are optimistic and plan further study.

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