Analysis of neurons created from wild-type and Alzheimer's mutation knock-in embryonic stem cells by a highly efficient differentiation protocol

Yoichiro Abe, Keisuke Kouyama, Taisuke Tomita, Yusuke Tomita, Norimitsu Ban, Mikiro Nawa, Masaaki Matsuoka, Takako Niikura, Sadakazu Aiso, Yoshiko Kita, Takeshi Iwatsubo, Ikuo Nishimoto

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

It is impossible to obtain and amplify live neurons from Alzheimer's disease (AD) patients. To establish the neurons harboring AD abnormality, we constructed mouse embryonic stem (ES) cells, in which the AD-causative V642I mutation was introduced to the endogenous amyloid precursor protein (APP) gene, in combination with a protocol to efficiently differentiate ES cells into postmitotic neurons without using a cell sorter. By this protocol, ES cells differentiated into >90% of the central type of adult postmitotic neurons. Neurons derived from V642I-APP knock-in ES cells were indistinguishable from wild-type ES-derived neurons, as determined by the expression of various markers for neuronal differentiation. Notably, V642I-APP knock-in ES cell-derived neurons exhibited significantly increased secretion of Aβ42 without AD-related hyperphosphorylation of tau, indicating that the direct output of the AD-causative mutation is increased Aβ42 secretion. In this study, we analyze created neurons with wild-type and AD genotypes and propose a new strategy for generating neurons for any dominantly inherited neurodegenerative diseases. The strategy can be applied to create human neurons with AD or any other neurodegenerative disease by using human ES cells.

Original languageEnglish
Pages (from-to)8513-8525
Number of pages13
JournalJournal of Neuroscience
Volume23
Issue number24
Publication statusPublished - 2003 Sep 17

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Amyloid-β protein
  • Differentiation
  • Embryonic stem cell
  • Gene knock-in
  • Postmitotic neuron
  • Sharable neuron with disease genotype
  • Tau

ASJC Scopus subject areas

  • Neuroscience(all)

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    Abe, Y., Kouyama, K., Tomita, T., Tomita, Y., Ban, N., Nawa, M., Matsuoka, M., Niikura, T., Aiso, S., Kita, Y., Iwatsubo, T., & Nishimoto, I. (2003). Analysis of neurons created from wild-type and Alzheimer's mutation knock-in embryonic stem cells by a highly efficient differentiation protocol. Journal of Neuroscience, 23(24), 8513-8525.