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

被引：15

作者：

Shimada, Hiroko ^{[1
]}

Sato, Yuta ^{[2
]}

Sasaki, Takashi ^{[3
]}

Shimozawa, Aki ^{[1
,4
]}

Imaizumi, Kent ^{[1
]}

Shindo, Tomoko ^{[5
]}

Miyao, Sachiyo ^{[1
]}

Kiyama, Kosuke ^{[1
]}

Kondo, Takahiro ^{[1
]}

Shibata, Shinsuke ^{[1
,5
,7
]}

Ishii, Seiji ^{[1
,8
]}

Kuromitsu, Junro ^{[1
,6
]}

Aoyagi, Hirofumi ^{[1
,6
]}

Ito, Daisuke ^{[1
]}

Okano, Hideyuki ^{[1
]}

机构：

[1] Keio Univ, Dept Physiol, Sch Med, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

[2] Keio Univ, Grad Sch Sci & Technol, Kohoku Ku, 3-14-1 Hiyoshi, Yokohama, Kanagawa 2238522, Japan

[3] Keio Univ, Ctr Supercentenarian Med Res, Sch Med, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

[4] Keio Univ, Ctr Integrated Med Res, Sch Med, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

[5] Keio Univ, Electron Microscope Lab, Sch Med, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

[6] Eisai & Co Ltd, Eisai Keio Innovat Lab Dementia, Hhc Data Creat Ctr, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

[7] Niigata Univ, Grad Sch Med & Dent Sci, Div Microscop Anat, Niigata, Japan

[8] Keio Univ, Dept Anat, Sch Med, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan

来源：

CELL REPORTS METHODS | 2022年 / 2卷 / 09期

关键词：

FRONTOTEMPORAL DEMENTIA; P301L TAU; INDUCTION; DISEASE; CELLS; MICE;

D O I：

10.1016/j.crmeth.2022.100289

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

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-b 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.

引用

页数：19

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