Brain immune cells destroy neurons in ALS
In ALS, motor neurons die. New mouse research suggests the disease itself is not the only driver: specific brain immune cells appear to actively consume still-living neurons, accelerating the loss.
ALS (amyotrophic lateral sclerosis) is a severe condition in which motor neurons progressively degenerate, leading to muscle weakness and loss of movement. Its precise causes are not yet fully understood.
Researchers focused on microglia, the immune cells of the brain and spinal cord. In healthy tissue, microglia clear dead cells and debris. The study, published in Nature Communications, shows in a mouse model that microglia in ALS tissue appear to actively engulf living motor neurons. The mechanism centres on two proteins on the cell surface: Axl and Mertk. These proteins recognise a signal that normally only appears on dying cells: phosphatidylserine, a kind of ‘eat me’ flag, which was abnormally elevated on the surface of ALS motor neurons.
What disabling Axl and Mertk achieved
When the Axl and Mertk genes were inactivated in the ALS mouse model, the animals lived longer. Motor neurons were better preserved, and neuromuscular synapses, the connections between nerve cells and muscles, remained intact for longer. The lysosomes of microglia, the cell’s internal waste compartments, also accumulated far fewer remnants of nerve cells.
This suggests that microglia in ALS tissue actively accelerate neuronal loss, rather than simply reacting to cell death that is already underway.
A note of caution
ALS mouse models are useful but limited. They rely on specific genetic mutations that mimic the disease in mice, and it is not certain that the same mechanism operates identically in humans. The researchers acknowledge this explicitly.
Still, the potential of this finding is considerable: if Axl and Mertk are the switch by which microglia destroy living neurons, these proteins are in principle targetable for future therapies. That makes this research relevant beyond ALS, across the broader field of neurodegenerative disease.
Search terms: microglia neuronal phagocytosis ALS, TAM receptor neurodegeneration, phosphatidylserine eat-me signal