Alexander Disease (AxD) is a rare neurodegenerative disease which is caused by dominant gain of function mutations in the GFAP gene. In AxD astrocytes show reactive phenotype with Rosenthal fibers which comprise of GFAP accumulations with aB-crystalline. Although AxD is thought to be an astrogliopathy, emerging evidence indicates that the inflammatory response including the microglial activation is induced in AxD. Accordingly, we previously observed the increase in the number of Iba1-positive microglia in the hippocampus from hemizygotes of 60TM AxD model mice which express human GFAP with R239H mutation (60TM mice). To understand the role of microglia in AxD, we depleted microglia from 60TM mice by treatment with PLX5622 (PLX), a CSF-1 receptor antagonist, between P21 and P42. PLX eliminated almost all Iba1-positive signals and its mRNA level in the hippocampus. Surprisingly, PLX increased GFAP staining and Fluoro-Jade B staining, suggesting exacerbation of AxD pathogenesis. PLX also augmented mRNA levels of reactive astrocyte markers such as Vim, C3 and Cd44. These data suggest that microglia may play a beneficial role in AxD pathogenesis by restraining the astrocyte to show reactive phenotype in this AxD model at early-developmental stage.