Alexander disease (AxD), a rare neurodegenerative disease, is caused by the mutation of GFAP gene (Brenner et al., Nat Genet., 2001) encoding glial fibrillary acidic protein (GFAP) which is enriched in astrocytes. Thus, AxD is a primary astrocyte disease. AxD patients mainly show severe neurological symptoms such as psychomotor developmental delay, motor deficits etc. with white matter disorders (leukodystrophy). However, molecular pathogenesis that leads from astrocytic mutations to leukodystrophy and further to these clinical manifestations are not well understood. Here, we show that AxD astrocytes directly cause demyelination in corpus callosum (CC) using AxD model mice carrying human mutant GFAP with R239H (Tanaka et al., GLIA, 2007). First, we found by immunohistochemical analysis that myelinated area stained with either myelin basic protein or proteolipid protein in CC was markedly decreased in AxD compared to wild-type (WT) mice. Second, the number of astrocytes was increased in CC of AxD compared to WT. In addition, AxD astrocytes with Rosenthal fiber, a hallmark of AxD, were highly accumulated in demyelinated area. Such astrocytic accumulation was not observed in CC of WT. These spatial correlation of AxD astrocytes with demyelination of CC would suggest that pathological astrocytes may be directly involved in local demyelination in CC. Third, we performed RNAseq analysis of AxD astrocytes and found that Galectin-3 and lipocalin 2 (Lcn2) were the top 10 most up-regulated genes (Saito & Shigetomi et al., GLIA, 2018). Interestingly, both Galectin-3 (Morizawa et al, Nat Commun., 2017) and Lcn2 (Wan et al., Nat Commun., 2022) could positively control astrocytic phagocytosis. Together, all these findings suggest that AxD astrocytes may cause demyelination by acquiring their abnormal phagocytic ability in CC, thereby leading to leukodystrophy and various neurological symptoms.