Microglial heterogeneity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease of the central nervous system that is pathologically characterized by motor neuron loss. Although the cause of the disease is still unknown, its pathophysiology is considered heterogeneous. In recent years, there have been a series of reports on the existence of disease-associated microglia (DAM) in the lesions of various neurodegenerative diseases. DAM have also been reported in SOD1-deficient mice, a disease model of ALS. However, the role of DAM in sporadic ALS remains unclear. This study revealed that spinal cord lesions in ALS can be pathologically distinguished into 2 subgroups (TMEM119+ and TMEM119- microglia) according to the type of microglia. Expression of the microglial activation marker CD68 and endothelial activation were also observed in the TMEM119+ microglia group, suggesting the presence of inflammatory processes in ALS lesions. Since DAM suppress the expression of TMEM119, the TMEM119+ microglia group may indicate DAM-independent inflammatory neurodegeneration. These results may explain why, in some clinical trials of anti-inflammatory drugs for ALS, only some cases showed suppression of disease progression.