Microglial replacement ameliorates Rosenthal fiber accumulation in Alexander disease, a primary astrocyte disease.

Alexander disease (AxD) is a rare neurodegenerative disease caused by the pathogenic variants of GFAP, an astrocyte-specific intermediate filament. This resulted in the formation of aberrant inclusions within astrocytes called Rosenthal Fibers (RFs), one of the main pathological hallmarks. In addition, activation of microglia (MG) is also observed in the AxD brain. We previously reported a beneficial role of MG using the AxD model mice, overexpressing mutant human GFAP. Here, we enhanced this beneficial function of MG by replacing MG using PLX5622 (PLX), a CSF-1R antagonist. Turning PLX ON and OFF causes MG removal and repopulation respectively (Rep), which allows us to replace old MG with repopulated MG (Rp-MG) in the AxD mice. Interestingly, the RFs were significantly reduced by Rep, indicating that Rep rescued the AxD pathology. We further analyzed the bulk RNA-sequencing data and found that lysosomal and phagocytic pathways were highly enhanced by Rep. Additional histological analysis revealed that Rp-MG strongly expressed CD68 and engulfed RFs, suggesting Rep could increase MG phagocytic capacity to remove RFs. Overall, the MG replacement could restore the AxD pathology by increasing their phagocytic capacity against RFs.