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：我的研究目标是 iPSC 衍生的星形胶质细胞的外泌体、iPSC 分化为星形胶质细胞和神经元以及神经祖细胞在小鼠体内的植入。目的是在体外研究可以解释 Kii ALS/PDC 这种特殊神经退行性疾病的机制，并在体内开发可用于药物测定的嵌合小鼠模型，以支持 Kii ALS/PDC 的研究。研究结果：2022财年是实验定稿、文章写作和修改的一年。我可以成功地在对照供体的人类脊髓中观察到对星形细胞线粒体呼吸至关重要的蛋白质，并且可以评估 Kii ALS/PDC 患者中该蛋白质的减少。我还可以根据 Kii ALS/PDC 患者的临床分层，在 RNA 水平上量化 Tau 亚型的显着减少。我还可以使用我们实验室发布的方法（Sato et al. Neurosci Lett 2021）将来自 3 名健康供体和 6 名患者的 iPSC 区分为几种神经元亚型。最后，我将神经胶质祖细胞移植到几只 NOD/SCID 小鼠中并进行了行为实验。对 iPSC 衍生的星形胶质细胞进行外泌体分析后，蛋白质组分析揭示了一组基因，表明对 iPS 衍生的 Kii ALS/PDC 星形胶质细胞具有有害作用，与之前发表的结果相一致（提交中的文章）。我还植入了来自 3 个对照系和 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