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

研究成果: Article査読

抄録

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.

本文言語English
論文番号100289
ジャーナルCell Reports Methods
2
9
DOI
出版ステータスPublished - 2022 9月 19

ASJC Scopus subject areas

  • バイオテクノロジー
  • 生化学
  • 生化学、遺伝学、分子生物学(その他)
  • 遺伝学
  • 放射線学、核医学およびイメージング
  • コンピュータ サイエンスの応用

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