A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer

Hiroko Shimada; Yuta Sato; Takashi Sasaki; Aki Shimozawa; Kent Imaizumi; Tomoko Shindo; Sachiyo Miyao; Kosuke Kiyama; Takahiro Kondo; Shinsuke Shibata; Seiji Ishii; Junro Kuromitsu; Hirofumi Aoyagi; Daisuke Ito; Hideyuki Okano

doi:10.1016/j.crmeth.2022.100289

A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer

Hiroko Shimada, Yuta Sato, Takashi Sasaki, Aki Shimozawa, Kent Imaizumi, Tomoko Shindo, Sachiyo Miyao, Kosuke Kiyama, Takahiro Kondo, Shinsuke Shibata, Seiji Ishii, Junro Kuromitsu, Hirofumi Aoyagi, Daisuke Ito, Hideyuki Okano

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

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.

Original language	English
Article number	100289
Journal	Cell Reports Methods
Volume	2
Issue number	9
DOIs	https://doi.org/10.1016/j.crmeth.2022.100289
Publication status	Published - 2022 Sept 19

Keywords

AAV
Alzheimer's disease
FGF2
brain organoids
feeder-free iPSCs
tau
tauopathy

ASJC Scopus subject areas

Biotechnology
Biochemistry
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Genetics
Radiology Nuclear Medicine and imaging
Computer Science Applications

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.crmeth.2022.100289

Cite this

Shimada, H., Sato, Y., Sasaki, T., Shimozawa, A., Imaizumi, K., Shindo, T., Miyao, S., Kiyama, K., Kondo, T., Shibata, S., Ishii, S., Kuromitsu, J., Aoyagi, H., Ito, D., & Okano, H. (2022). A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer. Cell Reports Methods, 2(9), Article 100289. https://doi.org/10.1016/j.crmeth.2022.100289

Shimada, H, Sato, Y, Sasaki, T, Shimozawa, A, Imaizumi, K, Shindo, T, Miyao, S, Kiyama, K, Kondo, T, Shibata, S, Ishii, S, Kuromitsu, J, Aoyagi, H, Ito, D & Okano, H 2022, 'A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer', Cell Reports Methods, vol. 2, no. 9, 100289. https://doi.org/10.1016/j.crmeth.2022.100289

@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 = "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",

}

TY - JOUR

T1 - A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer

AU - Shimada, Hiroko

AU - Sato, Yuta

AU - Sasaki, Takashi

AU - Shimozawa, Aki

AU - Imaizumi, Kent

AU - Shindo, Tomoko

AU - Miyao, Sachiyo

AU - Kiyama, Kosuke

AU - Kondo, Takahiro

AU - Shibata, Shinsuke

AU - Ishii, Seiji

AU - Kuromitsu, Junro

AU - Aoyagi, Hirofumi

AU - Ito, Daisuke

AU - Okano, Hideyuki

PY - 2022/9/19

Y1 - 2022/9/19

N2 - 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.

AB - 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.

KW - AAV

KW - Alzheimer's disease

KW - FGF2

KW - brain organoids

KW - feeder-free iPSCs

KW - tau

KW - tauopathy

UR - http://www.scopus.com/inward/record.url?scp=85138116349&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85138116349&partnerID=8YFLogxK

U2 - 10.1016/j.crmeth.2022.100289

DO - 10.1016/j.crmeth.2022.100289

M3 - Article

C2 - 36160042

AN - SCOPUS:85138116349

SN - 2667-2375

VL - 2

JO - Cell Reports Methods

JF - Cell Reports Methods

IS - 9

M1 - 100289

ER -

A next-generation iPSC-derived forebrain organoid model of tauopathy with tau fibrils by AAV-mediated gene transfer

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this