研究者業績データベース | 公益財団法人東京都医学総合研究所研究者業績データベース

※ をクリックすると外部の論文のサイトが開きます。

キーワード

※ スペース区切りで絞り込み検索が可能です。

種別

論文

タイトル: 「一次性アストロサイト病」アレキサンダー病におけるミクログリアの病態関連機序の解明
タイトル（英）: The mechanisms of which microglia are related to the pathology in the "primary astrocytic disease" Alexander disease.
参照URL: https://researchmap.jp/read0091842/published_papers/44307146
著者: 齋藤光象,繁冨英治,篠崎陽一,パラジュリビジェイ,小泉修一
著者（英）: Saito Kozo,Shigetomi Eiji,Shinozaki Youichi,Parajuli Bijay,Koizumi Schuichi
担当区分
概要: 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.
概要（英）: 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.
出版者・発行元: 公益社団法人日本薬理学会
出版者・発行元（英）: Japanese Pharmacological Society
誌名: 日本薬理学会年会要旨集
誌名（英）: Proceedings for Annual Meeting of The Japanese Pharmacological Society
巻: 96
号
開始ページ: YIA08-5
終了ページ
出版年月: 2022年
査読の有無
招待の有無
掲載種別
ISSN
DOI URL: https://doi.org/10.1254/jpssuppl.96.0_yia08-5
共同研究・競争的資金等の研究課題

研究者

篠﨑陽一 (シノザキヨウイチ)