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：我的研究针对来自IPSC衍生的星形胶质细胞，IPSC分化为星形胶质细胞和神经元的外泌体以及小鼠神经祖细胞的植入。目的是在体外调查一种可以解释这种特殊的神经退行性疾病kii als/pdc的机制，并且在体内开发可用于药物分析的嵌合小鼠模型，以支持对KII ALS/PDC-Patients的研究。研究结果：FY2022的研究是FY2022的一年，是一年级的经验。我可以从控制供体中成功地在人脊髓中形象化一个蛋白质的蛋白质至关重要，用于星形胶质细胞的呼吸，并可以评估KII ALS/PDC患者中它的降低。我还可以在RNA水平上量化Tau同工型的显着降低，这取决于KII ALS/PDC患者的临床分层。我还可以使用在我们的实验室中发表的方法将IPSC与3名健康供体和6例患者区分为几种亚型神经元（Sato等人Neurosci Lett 2021）。最后，我用神经胶质祖细胞和进行行为实验植入了几只点头/SCID小鼠。在从IPSC衍生的星形胶质细胞中进行了外泌体分析后，蛋白质组分析显示了一组基因，表明IPS来源的KII ALS/PDC-腹腔细胞具有有害作用，与先前发表的结果一致（列出的文章）。我还植入了3个控制线和3例患者的神经祖细胞，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