دورية أكاديمية
Microglia sense astrocyte dysfunction and prevent disease progression in an Alexander disease model.
| العنوان: | Microglia sense astrocyte dysfunction and prevent disease progression in an Alexander disease model. |
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| المؤلفون: | Saito K; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.; GLIA Center, University of Yamanashi, Yamanashi 409-3898, Japan., Shigetomi E; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.; GLIA Center, University of Yamanashi, Yamanashi 409-3898, Japan., Shinozaki Y; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.; GLIA Center, University of Yamanashi, Yamanashi 409-3898, Japan., Kobayashi K; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan., Parajuli B; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.; GLIA Center, University of Yamanashi, Yamanashi 409-3898, Japan., Kubota Y; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan., Sakai K; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.; GLIA Center, University of Yamanashi, Yamanashi 409-3898, Japan., Miyakawa M; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.; GLIA Center, University of Yamanashi, Yamanashi 409-3898, Japan., Horiuchi H; Division of Homeostatic Development, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi 444-8585, Japan., Nabekura J; Division of Homeostatic Development, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi 444-8585, Japan., Koizumi S; Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.; GLIA Center, University of Yamanashi, Yamanashi 409-3898, Japan. |
| المصدر: | Brain : a journal of neurology [Brain] 2024 Feb 01; Vol. 147 (2), pp. 698-716. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Oxford University Press Original Publication: London. |
| مواضيع طبية MeSH: | Alexander Disease*/metabolism , Alexander Disease*/pathology, Mice ; Animals ; Glial Fibrillary Acidic Protein/metabolism ; Astrocytes/metabolism ; Microglia/metabolism ; Clopidogrel/metabolism ; Calcium/metabolism ; Disease Progression ; Adenosine Triphosphate/metabolism |
| مستخلص: | 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. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.) |
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| معلومات مُعتمدة: | JP17K01974 JSPS KAKENHI; JP20gm1310008 AMED-CREST; OPERA |
| فهرسة مساهمة: | Keywords: Alexander disease; astrocyte-microglia interactions; microglial ca2+ signal; single-cell RNA sequencing; two-photon imaging |
| المشرفين على المادة: | 0 (Glial Fibrillary Acidic Protein) A74586SNO7 (Clopidogrel) SY7Q814VUP (Calcium) 8L70Q75FXE (Adenosine Triphosphate) |
| تواريخ الأحداث: | Date Created: 20231113 Date Completed: 20240205 Latest Revision: 20240306 |
| رمز التحديث: | 20240307 |
| مُعرف محوري في PubMed: | PMC10834242 |
| DOI: | 10.1093/brain/awad358 |
| PMID: | 37955589 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1460-2156 |
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| DOI: | 10.1093/brain/awad358 |