Microglia have a high capacity to repopulate in the adult brain. Microglial survival requires signaling via the colony-stimulating factor 1 receptor (CSF1R), and the removal/repopulation of microglia can be triggered by turning ON/OFF of CSF1R antagonists. Using this microglial replacement protocol ("reset"), we show its therapeutic effect on Alexander disease (AxD). AxD is a primary astrocytic disease caused by mutations in GFAP, but microglial activation occurs in the AxD brain as well. It is well known that many neurodegenerative and psychiatric diseases are accompanied by microglial activation, leading to neuroinflammation. Therefore, removal of microglia is considered one of the strategies for the treatment of these diseases. However, we found that microglial removal with CSF1R antagonists exersavated AxD pathology. This suggests that microglia, or at least some populations of them, play a beneficial role in AxD pathology. We found that reset, but not elimination of microglia ameliorated AxD pathology. Thus, we suggest that microglial replacement may be a better therapeutic strategy for AxD and possibly for other neurological diseases. We also report on the mechanisms underlying the therapeutic effect via microglial reset by RNAseq analysis.