Scientists have uncovered the role of immune cells in the destruction of neurons in ALS

Amyotrophic lateral sclerosis (ALS) gradually destroys motor neurons— the nerve cells that transmit signals from the brain to the muscles. Now researchers have discovered an unexpected mechanism for this process: microglia, immune cells of the brain and spinal cord, can use a special system to recognize and destroy still-living neurons. About how microglia cause cells to give a false signal for destruction and why blocking this mechanism gave an ambiguous result is in the Izvestia article.

Microglia received a signal for destruction

For a long time, the main focus of ALS research has been on motor neurons. However, microglia — immune cells located in the brain and spinal cord — also become very active during the disease. Researchers from the Salk Institute decided to find out why this is happening. The results of the work are published on the Medical Xpress portal.

The scientists focused on TAM receptors, a family of proteins that are involved in the removal of dying cells. Normally, dying cells exhibit a kind of "eat me" signal on their surface, which is recognized by the TAM system. The researchers suggested that in ALS, this mechanism may not work properly and direct microglia against still-living neurons.

Living neurons have become the target of microglia

To test the hypothesis, the scientists used the most common mouse model of ALS, SOD1. Such animals carry the mutant protein SOD1, which causes ALS in humans. The researchers found that in the spinal cord of SOD1 mice, many motor neurons had already been absorbed by microglia. At the same time, the level of TAM proteins, especially Axl and Mer, was increased in animals.

In a more detailed study of neurons, scientists found phosphatidylserine on their surface — the very molecules that should serve as a signal for cell removal. The problem was that these "eating signals" appeared on cells that had not yet died. The TAM system directed microglia to them, after which the immune cells absorbed the living neurons.

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The available reserves will last for six months, Roszdravnadzor said.

Removal of TAM proteins changed the course of the disease

The researchers then tested what would happen if two proteins of the TAM family, Axl and Mer, were removed. The result was unexpected: the mice got sick faster after that, but lived longer.

The condition of the microglia itself has also changed. In the spinal cord of SOD1 mice, these cells were filled with absorbed neurons, but after the TAM system was turned off, such accumulation decreased dramatically. Thus, the researchers concluded that microglia use the TAM system to kill cells that have not yet died.

The discovery can be useful not only for ALS

The results obtained help to explain how microglial activity is associated with progression and death in ALS. However, scientists do not believe that simply removing the TAM system will be the optimal treatment option.

At the same time, the work has opened up another potential direction — the use of the TAM system in immunotherapy. After scientists showed that this mechanism is able to direct microglia to living cells, research groups in Japan and South Korea developed TAM proteins that allow them to tag specific cells and attract microglia to them. In experiments, one of these proteins helped to destroy live B cells in mice with lupus, and the other - live cancer cells and reduce the growth of melanoma tumors.

According to the authors, this approach could potentially become an alternative to more complex cellular immunotherapies.: Instead of creating whole cells, it will be possible to develop TAM proteins aimed at the desired cell type.