Anti-Aβ drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease

Naoki Yahata, Masashi Asai, Shiho Kitaoka, Kazutoshi Takahashi, Isao Asaka, Hiroyuki Hioki, Takeshi Kaneko, Kei Maruyama, Takaomi C. Saido, Tatsutoshi Nakahata, Takashi Asada, Shinya Yamanaka, Nobuhisa Iwata, Haruhisa Inoue

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Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease. Methodology/Principal Findings: We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, β-secretase, and γ-secretase components, and were capable of secreting Aβ into the conditioned media. Aβ production was inhibited by β-secretase inhibitor, γ-secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (Aβ surge) and drastic decline of Aβ production. Conclusions/Significance: These results indicate that the hiPS cell-derived neuronal cells express functional β- and γ-secretases involved in Aβ production; however, anti-Aβ drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation.

Original languageEnglish
Article numbere25788
JournalPloS one
Volume6
Issue number9
DOIs
Publication statusPublished - 30-09-2011

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Yahata, N., Asai, M., Kitaoka, S., Takahashi, K., Asaka, I., Hioki, H., Kaneko, T., Maruyama, K., Saido, T. C., Nakahata, T., Asada, T., Yamanaka, S., Iwata, N., & Inoue, H. (2011). Anti-Aβ drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease. PloS one, 6(9), [e25788]. https://doi.org/10.1371/journal.pone.0025788