In ALS, immune cells consume living neurons

Microglia are the resident immune cells of the brain and spinal cord. Their job is to clear damaged or dead cells. They identify a target through a specific signal: a lipid called phosphatidylserine (PtdSer), which normally lines the inside of the cell membrane. When a cell dies, PtdSer flips to the outside, telling microglia to engulf it.

In ALS patients, this system appears to misfire severely. The researchers examined postmortem spinal cord tissue from six people with sporadic ALS and three age-matched controls. Two key proteins in the recognition system, the TAM receptors AXL and MER, were dramatically elevated in ALS patients. AXL was approximately sixteen times higher; MER roughly three times higher.

Living cells wearing a false death signal

The team confirmed this pattern in a mouse model of ALS. As the disease progressed, AXL and MER activity in microglia increased. At the same time, motor neurons in sick mice showed large amounts of phosphatidylserine on the outside of their membranes. In healthy animals, this signal was nearly absent.

The conclusion is striking: the motor neurons were not dead, yet they displayed the signal that tells microglia they are. Under cellular stress, cells can temporarily expose this signal without intending to die. Microglia respond regardless and destroy cells that might otherwise have survived.

What this means for aging

ALS predominantly affects people later in life. The finding that the TAM system can become dysregulated with aging is noteworthy from a longevity perspective: similar patterns of overactive microglia have been suggested in other neurodegenerative conditions, including Parkinson’s and Alzheimer’s. Whether blocking this signaling pathway would be protective remains to be tested. The researchers suggest the TAM system could be a therapeutic target, but clinical evidence is currently lacking.

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