Glia in Neurodegenerative Diseases: a Human Glial Chimeric Mouse Model

神经退行性疾病中的神经胶质细胞：人类神经胶质细胞嵌合小鼠模型

• 批准号: 22KF0333
• 负责人: 岡野 栄之
• 金额: $ 1.47万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2023
• 资助国家: 日本
• 起止时间: 2023-03-08 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22KF0333/
• 关键词: Kii ALS/PDC; iPSC; Astrocytes; MAPT isoforms; Chimeric mouse model; astrocytes

Research aim:My research targets exosomes from iPSC-derived astrocytes, iPSC differentiation into astrocytes and neurons and engraftment of neural progenitors in mice. The purpose is to investigate in vitro a mechanistic that could explain this peculiar neurodegenerative disease Kii ALS/PDC is, and in vivo to develop a chimeric mouse model which could be used for drugs assays, in order to support research to Kii ALS/PDC-patients.Research results:FY2022 has been the year of finalization of the experiments, writing of the article and revisions too. I could successfully visualize in human spinal cord from control-donors a protein paramount for astrocytic-mitochondria respiration and could assess a decrease of it in Kii ALS/PDC-patients. I could also quantify at RNA level a significant decrease in Tau isoforms depending on the clinical stratification of Kii ALS/PDC-patients. I could also differentiate iPSC from 3 healthy donors and 6 patients into several sub-type of neurons using a method published in our Lab (Sato et al. Neurosci Lett 2021). Finally, I have engrafted several NOD/SCID mice with glial progenitors and performed behavioral experiments. After having performed exosomes analysis from iPSC-derived astrocytes, proteome analysis revealed a set of genes indicative of a deleterious effect in iPS-derived Kii ALS/PDC-astrocytes, concomitant with previous published results (article in submission). I also engrafted neural progenitors from 3 control lines and 3 patients and performed behavioral analysis.

研究目的：研究iPSC来源的星形胶质细胞外泌体，iPSC向星形胶质细胞和神经元的分化以及神经祖细胞在小鼠体内的移植。目的是在体外研究这种特殊的神经退行性疾病Kii ALS/PDC的发病机制，并在体内建立可用于药物检测的嵌合小鼠模型，为Kii ALS/PDC患者的研究提供支持。研究成果：2022财年是实验结题、文章撰写和修改的一年。我可以成功地在对照供体的人类脊髓中看到一种对星形细胞线粒体呼吸至关重要的蛋白质，并可以评估Kii ALS/ pdc患者中这种蛋白质的减少。我还可以在RNA水平上量化Tau亚型的显著减少，这取决于Kii ALS/ pdc患者的临床分层。我还可以使用我们实验室发表的方法将来自3名健康供体和6名患者的iPSC分化为几种亚型神经元（Sato等人）。神经科学Lett 2021)。最后，我将几只NOD/SCID小鼠植入了神经胶质祖细胞，并进行了行为实验。在对ipsc衍生的星形胶质细胞进行外泌体分析后，蛋白质组学分析揭示了一组基因，表明ipsc衍生的Kii ALS/ pdc星形胶质细胞具有有害作用，与先前发表的结果一致（文章提交）。我还移植了3个控制系和3个患者的神经祖细胞，并进行了行为分析。

项目成果

Establishment of KEIOi005-A iPSC line from urine-derived cells (UDCs) of a mild Alzheimer's disease (AD) donor with multiple risk SNPs for sporadic Alzheimer's disease (sAD)

利用轻度阿尔茨海默病 (AD) 供体的尿源性细胞 (UDC) 建立 KEIOi005-A iPSC 系，该细胞具有散发性阿尔茨海默病 (SAD) 的多个风险 SNP

• DOI: 10.1016/j.scr.2022.102802
• 发表时间: 2022
• 期刊: Stem Cell Res .
• 作者: Sopak Supakul;Nicolas Leventoux;Hajime Tabuchi;Masaru Mimura;Daisuke Ito;Sumihiro Maeda;Hideyuki Okano
• 通讯作者: Hideyuki Okano

Astrogliopathy is caused by mitochondrial abnormalities in amyotrophic lateral sclerosis and Parkinsonism-dementia complex of the Kii peninsula

星形神经胶质病是由纪伊半岛肌萎缩侧索硬化症和帕金森痴呆症复合体的线粒体异常引起的

• 发表时间: 2021
• 作者: Nicolas Leventoux;Satoru Morimoto;Mitsuru Ishikawa;Fumito Endo;Shinsuke Shibata;Koji Yamanaka;Shigeki Kuzuhara;Yasumasa Kokubo;Hideyuki Okano
• 通讯作者: Hideyuki Okano

iPSC technology reveals mitochondrial abnormalities cause of astrogliopathy in patients with amyotrophic lateral sclerosis and Parkinsonism-dementia complex in the Kii peninsula

iPSC 技术揭示了纪伊半岛肌萎缩侧索硬化症和帕金森痴呆症患者星形胶质细胞病的线粒体异常原因

• 发表时间: 2021
• 作者: Nicolas Leventoux;Satoru Morimoto;Mitsuru Ishikawa;Fumito Endo;Shinsuke Shibata;Koji Yamanaka;Shigeki Kuzuhara;Yasumasa Kokubo;Hideyuki Okano
• 通讯作者: Hideyuki Okano

IPSC TECHNOLOGY REVEALS MITOCHONDRIAL DEFECTS CAUSE OF ASTROGLIOPATHY IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS AND PARKINSONISM-DEMENTIA COMPLEX IN THE KII PENINSULA.

IPSC 技术揭示了纪伊半岛肌萎缩侧索硬化症和帕金森痴呆症患者星形胶质病的线粒体缺陷原因。

• 发表时间: 2021
• 作者: Nicolas Leventoux;Satoru Morimoto;Mitsuru Ishikawa;Fumito Endo;Shinsuke Shibata;Koji Yamanaka;Shigeki Kuzuhara;Yasumasa Kokubo;Hideyuki Okano
• 通讯作者: Hideyuki Okano