Alexander disease (AxD) is a rare neurological disorder caused by mutations of GFAP gene, an astrocyte selective intermediate filament, and AxD astrocytes show abnormal aggregates, i.e., Rosenthal fibers (RFs), a main pathological finding. AxD brain also shows neuroinflammation, where microglia are activated.　In this study, we show that manipulation of microglia would be a potential therapeutic strategy for the treatment of AxD using AxD model mice with human GFAP mutation (R239H) (60TM), To achieve this, we used an ON/OFF protocol of PLX5622 (PLX), a selective CSF-1 receptor antagonist. PLX-ON depleted almost all resident microglia, and subsequent PLX-OFF caused almost complete recovery of microglia, indicating that the old microglia should be replaced with newly repopulated microglia in the AxD brain. The amount of RF stained with Fluoro Jade B was significantly reduced by this replacement, suggesting that microglia should become more protective by their repopulation. Furthermore, microglial replacement significantly decreased the expression of Lipocalin2, the most upregulated molecule in 60TM astrocyte, and other inflammatory molecules in 60TM. Taken together, the ON/OFF protocol of PLX allows us to replace old microglia with newly repopulated ones in the AxD brain, which can dramatically ameliorate AxD pathogenesis.