@article{186e91f242b7438c8282b7fc41f964ca,
title = "A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer",
abstract = "It is known that the human cellular models of Alzheimer's disease (AD) and tauopathy can only recapitulate the very early stage of the disease. To overcome these limitations, we developed a technology to make forebrain organoids (FBOs) from feeder-free induced pluripotent stem cells (iPSC)s by regulating a FGF2 concentration and applied this method to generate FBOs from patients with familial AD (fAD FBOs). The obtained fAD FBOs recapitulated the amyloid-β pathology and increased tau phosphorylation but not tau aggregates. To fully induce the tau pathology, FBOs were injected with adeno-associated virus (AAV)-expressing P301L mutant tau. In these Tau-P301L FBOs, tau fibrils were observed in the neuronal cell body and neurites with immunoelectron microscopy, in addition to the sarkosyl-insoluble and thioflavin S-positive phospho-tau aggregates. Collectively, this model can be used as a platform for investigating pathogenetic mechanisms and evaluation of target molecules for drug discovery for tauopathy.",
keywords = "AAV, Alzheimer's disease, FGF2, brain organoids, feeder-free iPSCs, tau, tauopathy",
author = "Hiroko Shimada and Yuta Sato and Takashi Sasaki and Aki Shimozawa and Kent Imaizumi and Tomoko Shindo and Sachiyo Miyao and Kosuke Kiyama and Takahiro Kondo and Shinsuke Shibata and Seiji Ishii and Junro Kuromitsu and Hirofumi Aoyagi and Daisuke Ito and Hideyuki Okano",
note = "Funding Information: We would like to thank Peter Davies at Albert Einstein College of Medicine for providing a MC1 antibody. We also thank Drs. Kazuhiro Sakurada, Jay W. Shin, Satoru Morimoto, Masaki Takao, Junko Hayashi, Mitsuru Ishikawa, Tomoko Andoh-Noda, Hirotaka Watanabe, Mie Furuhashi, Sumihiro Maeda, Mika Terumitsu, and Takuya Shimazaki (Keio University) for their helpful comments and support. We appreciate Profs. Hirofumi Suemori, Shinya Yamanaka, and Keisuke Okita (Kyoto University) for kindly providing hPSC lines KhES1, 201B7, and 414C2 respectively. This work was supported by the program for Regenerative Medicine (the Program for Intractable Disease Research Utilizing Disease-specific iPSCs and the Acceleration Program for Intractable Diseases Research Utilizing Disease-specific iPSCs), Practical Research Project for Rare/Intractable Diseases (H.O.) ( JP16ek0109013 , JP16ek0109158 , JP16bm0609003 , JP17bm0804003 , JP18bm0804003 , JP19bm0804003 , JP20bm0804003 , and JP21bm0804003 ), no. 17pc0101006 from the Japan Agency for Medical Research and Development, and research foundation from Eisai Co., Ltd . Funding Information: We would like to thank Peter Davies at Albert Einstein College of Medicine for providing a MC1 antibody. We also thank Drs. Kazuhiro Sakurada, Jay W. Shin, Satoru Morimoto, Masaki Takao, Junko Hayashi, Mitsuru Ishikawa, Tomoko Andoh-Noda, Hirotaka Watanabe, Mie Furuhashi, Sumihiro Maeda, Mika Terumitsu, and Takuya Shimazaki (Keio University) for their helpful comments and support. We appreciate Profs. Hirofumi Suemori, Shinya Yamanaka, and Keisuke Okita (Kyoto University) for kindly providing hPSC lines KhES1, 201B7, and 414C2 respectively. This work was supported by the program for Regenerative Medicine (the Program for Intractable Disease Research Utilizing Disease-specific iPSCs and the Acceleration Program for Intractable Diseases Research Utilizing Disease-specific iPSCs), Practical Research Project for Rare/Intractable Diseases (H.O.) (JP16ek0109013, JP16ek0109158, JP16bm0609003, JP17bm0804003, JP18bm0804003, JP19bm0804003, JP20bm0804003, and JP21bm0804003), no. 17pc0101006 from the Japan Agency for Medical Research and Development, and research foundation from Eisai Co. Ltd. Overall conceptualization, H.S. and H.O.; primary experimentation, H.S.; AAV injections, H.S. Y.S. A.S. K.K. T.K. and H.A.; immunohistochemistry, H.S. and S.M.; biochemistry, H.S. A.S. and H.A.; electron microscopy, T.S. and S.S.; gene-expression analysis, T.S. and K.I.; methodology, discussion, and investigation, H.S. A.S. H.A. S.I. J.K. and H.O.; writing – original draft, H.S.; writing – review & editing, all authors; funding acquisition, H.S. and H.O.; supervision and project administration, H.S. D.I. and H.O. H.O. is a scientific consultant for SanBio, Co. Ltd. and K Pharma, Inc. H.S. declares non-financial competing interests. H.A. and J.K. are full-time employees of Eisai, a pharmaceutical company listed on the Tokyo Stock Exchange (TYO:4523) for the period in which the data reported in this study were generated. Y.S. and T.K. are the founders of ALAN, Inc. and held shares in ALAN, Inc. There are two international patent applications related to this work, and these application numbers are PCT/JP2020/025605 (H.O. and H.S.) and PCT/JP2022/12502 (H.O. H.S. Y.S. and T.K.). Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = sep,
day = "19",
doi = "10.1016/j.crmeth.2022.100289",
language = "English",
volume = "2",
journal = "Cell Reports Methods",
issn = "2667-2375",
publisher = "Cell Press",
number = "9",
}