[Mechanism of Microglial Surveillance and Protection against Alexander Disease Pathology]

Alexander disease, also known as primary astrocyte disease, is a neurological disorder caused by mutations in the astrocyte-specific gene GFAP. The most prominent pathological finding is Rosenthal fiber formation within the astrocyte cytoplasm, which is primarily composed of GFAP and heat shock proteins (α-B crystalline, HPS27). Although astrocyte-derived changes may have widespread effects on the central nervous system, resulting in pathological changes and clinical manifestations, the etiological mechanisms of the disease remain underexplored. Our recent study focused on microglia, a type of glial cell, and showed that microglia actively participate in the pathophysiology of Alexander disease. In a mouse model of Alexander disease, we observed that microglia sense elevated extracellular adenosine triphosphate (ATP) produced by astrocytic pathology as a pathological signal through the P2Y12 receptor and suppress astrocyte pathology. Microglia have been shown to have important disease-modifying effects on Alexander disease. Overall, this study will contribute to the development of microglial manipulation-based therapies. In this review, we discuss the clinical features and experimental research on Alexander disease conducted to date. In addition, we discuss the topics of our recent study.