Alexander disease (AxD) is an intractable neurodegenerative disorder caused by GFAP mutations. AxD astrocytes show several abnormal phenotypes. Our previous study has shown that astrocytes in AxD model mice show aberrant Ca²⁺ signal that was a cause of etiology of AxD. In addition, using 2 photon imaging and Iba1-GCaMP6-60TM, an AxD model for microglial Ca²⁺ imaging, we recently found that microglial Ca²⁺ signals were also dramatically enhanced in the AxD model with more frequent Ca²⁺ signals in both the processes and cell bodies. Such increases in Ca²⁺ signals were inhibited by P2Y₁₂R antagonist but not by TTX, suggesting that these enhancement should be independent of neuronal activity, but dependent on extracellular ATP-mediated signals. Thus, we hypothesized that these microglial abnormal Ca²⁺ signals would be caused by increase of ATP amount released from astrocytes. Our analysis data of scRNAseq suggested that some astrocyte subclusters unique to the AxD model exhibit the lower expression level of the gene of astrocyte-specific ectonucleotidase subtype. In in situ ATP imaging using in vivo injection of AAV GfaABC1D ATP1.0, the signals of locally puffed ATP persisted longer in acute slice in AxD model than control WT mice, indicating a delay of ATP degradation in AxD brain that could cause the hyperactive Ca²⁺ signals in microglia. To study if these P2Y₁₂R-mediated Ca²⁺ signals in AxD microglia play any significant roles in the mechanism of pathology, P2Y₁₂R antagonist was administered. AxD model with treatment of P2Y₁₂R antagonist showed an exacerbation of pathological markers. This suggested that microglia play a protective role in AxD pathology via P2Y₁₂R. Our findings hold promise for the future development of therapies based on microglial manipulation.