Genetic background variation impacts microglial heterogeneity and disease progression in amyotrophic lateral sclerosis model mice

Recent single-cell analyses have revealed the complexity of microglial heterogeneity in brain development, aging, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Disease-associated microglia (DAMs) have been identified in ALS mice model, but their role in ALS pathology remains unclear. The effect of genetic background variations on microglial heterogeneity and functions remains unknown. Herein, we established and analyzed two mice models of ALS with distinct genetic backgrounds of C57BL/6 and BALB/c. We observed that the change in genetic background from C57BL/6 to BALB/c affected microglial heterogeneity and ALS pathology and its progression, likely due to the defective induction of neurotrophic factor-secreting DAMs and impaired microglial survival. Single-cell analyses of ALS mice revealed new markers for each microglial subtype and a possible association between microglial heterogeneity and systemic immune environments. Thus, we highlighted the role of microglia in ALS pathology and importance of genetic background variations in modulating microglial functions. We analyzed gene expressions in microglia isolated from spinal cords of SOD1G93A mice carrying a low copy number of mutant SOD1 and having C57BL/6JJcl or BALB/cAJcl genetical backgrounds by magnetic-activated cell sorting (MACS) at end-stage of disease.