Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.11477/mf.188160960770030281

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Peripheral infection induces inflammation in peripheral tissues and the brain, impacting brain function. Glial cells are key players in this process. However, the effects of peripheral infection on glial activation and brain function remain unknown. Here, we showed that varying degrees of peripheral infection had different effects on the regulation of brain functions by microglia-dependent and -independent mechanisms. Acute mild infection (one-day LPS challenge: 1LPS) exacerbated middle cerebral artery occlusion (MCAO) injury, and severe infection (four-day LPS challenge: 4LPS) for one week suppressed it. MCAO injury was assessed by triphenyltetrazolium chloride staining. We observed early activation of microglia in the 1LPS and 4LPS groups. Depleting microglia with a colony-stimulating factor-1 receptor (CSF1R) antagonist had no effect on 1LPS-induced brain injury exacerbation but abolished 4LPS-induced protection, indicating microglial independence and dependence, respectively. Microglia-independent exacerbation caused by 1LPS involved peripheral immune cells including macrophages. RNA sequencing analysis of 4LPS-treated microglia revealed increased factors related to anti-inflammatory and neuronal tissue repair, suggesting their association with the protective effect. In conclusion, varying degrees of peripheral inflammation had contradictory effects (exacerbation vs. protection) on MCAO, which may be attributed to microglial dependence. Our findings highlight the significant impact of peripheral infection on brain function, particularly in relation to glial cells.

DOI： 10.3390/ijms242417597

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Alexander disease (AxD) is an intractable neurodegenerative disorder caused by GFAP mutations. It is a primary astrocyte disease with a pathological hallmark of Rosenthal fibres within astrocytes. AxD astrocytes show several abnormal phenotypes. Our previous study showed that AxD astrocytes in model mice exhibit aberrant Ca2+ signals that induce AxD aetiology. Here, we show that microglia have unique phenotypes with morphological and functional alterations, which are related to the pathogenesis of AxD. Immunohistochemical studies of 60TM mice (AxD model) showed that AxD microglia exhibited highly ramified morphology. Functional changes in microglia were assessed by Ca2+ imaging using hippocampal brain slices from Iba1-GCaMP6-60TM mice and two-photon microscopy. We found that AxD microglia showed aberrant Ca2+ signals, with high frequency Ca2+ signals in both the processes and cell bodies. These microglial Ca2+ signals were inhibited by pharmacological blockade or genetic knockdown of P2Y12 receptors but not by tetrodotoxin, indicating that these signals are independent of neuronal activity but dependent on extracellular ATP from non-neuronal cells. Our single-cell RNA sequencing data showed that the expression level of Entpd2, an astrocyte-specific gene encoding the ATP-degrading enzyme NTPDase2, was lower in AxD astrocytes than in wild-type astrocytes. In situ ATP imaging using the adeno-associated virus vector GfaABC1D ATP1.0 showed that exogenously applied ATP was present longer in 60TM mice than in wild-type mice. Thus, the increased ATP level caused by the decrease in its metabolizing enzyme in astrocytes could be responsible for the enhancement of microglial Ca2+ signals. To determine whether these P2Y12 receptor-mediated Ca2+ signals in AxD microglia play a significant role in the pathological mechanism, a P2Y12 receptor antagonist, clopidogrel, was administered. Clopidogrel significantly exacerbated pathological markers in AxD model mice and attenuated the morphological features of microglia, suggesting that microglia play a protective role against AxD pathology via P2Y12 receptors. Taken together, we demonstrated that microglia sense AxD astrocyte dysfunction via P2Y12 receptors as an increase in extracellular ATP and alter their morphology and Ca2+ signalling, thereby protecting against AxD pathology. Although AxD is a primary astrocyte disease, our study may facilitate understanding of the role of microglia as a disease modifier, which may contribute to the clinical diversity of AxD.

DOI： 10.1093/brain/awad358

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Nature  

DOI： 10.1007/s11302-022-09918-7

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Other Link： https://link.springer.com/article/10.1007/s11302-022-09918-7/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neuropharm.2022.109302.

Event date： 2025.3

Language：Japanese   Presentation type：Poster presentation  

Venue：Chiba city  

Event date： 2024.9

Language：English   Presentation type：Oral presentation(general)  

Venue：Lausanne, Switzerland   Country：Switzerland  

Event date： 2024.7

Language：English   Presentation type：Oral presentation(general)  

Venue：Fukuoka city  

Event date： 2024.6

Language：Japanese   Presentation type：Oral presentation(general)  

Venue：オンライン  

Event date： 2024.5 - 2024.6

Language：Japanese   Presentation type：Symposium workshop panel(nominated)  

Venue：Nagoya city  

Author：Other 

Author：Other