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

Research output: Contribution to journalArticle

107 Citations (Scopus)

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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Induced Pluripotent Stem Cells
Amyloid Precursor Protein Secretases
Preclinical Drug Evaluations
Alzheimer disease
Stem cells
Neurons
Alzheimer Disease
Screening
neurons
screening
drugs
amyloid
Pharmaceutical Preparations
brain
Cells
Presenilins
nonsteroidal anti-inflammatory agents
neurodegenerative diseases
Non-Steroidal Anti-Inflammatory Agents
Conditioned Culture Medium

All Science Journal Classification (ASJC) codes

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

Cite this

Yahata, Naoki ; Asai, Masashi ; Kitaoka, Shiho ; Takahashi, Kazutoshi ; Asaka, Isao ; Hioki, Hiroyuki ; Kaneko, Takeshi ; Maruyama, Kei ; Saido, Takaomi C. ; Nakahata, Tatsutoshi ; Asada, Takashi ; Yamanaka, Shinya ; Iwata, Nobuhisa ; Inoue, Haruhisa. / Anti-Aβ drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease. In: PloS one. 2011 ; Vol. 6, No. 9.
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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.",
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Yahata, N, Asai, M, Kitaoka, S, Takahashi, K, Asaka, I, Hioki, H, Kaneko, T, Maruyama, K, Saido, TC, 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, vol. 6, no. 9, e25788. https://doi.org/10.1371/journal.pone.0025788

Anti-Aβ drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease. / Yahata, Naoki; Asai, Masashi; Kitaoka, Shiho; Takahashi, Kazutoshi; Asaka, Isao; Hioki, Hiroyuki; Kaneko, Takeshi; Maruyama, Kei; Saido, Takaomi C.; Nakahata, Tatsutoshi; Asada, Takashi; Yamanaka, Shinya; Iwata, Nobuhisa; Inoue, Haruhisa.

In: PloS one, Vol. 6, No. 9, e25788, 30.09.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Anti-Aβ drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer's disease

AU - Yahata, Naoki

AU - Asai, Masashi

AU - Kitaoka, Shiho

AU - Takahashi, Kazutoshi

AU - Asaka, Isao

AU - Hioki, Hiroyuki

AU - Kaneko, Takeshi

AU - Maruyama, Kei

AU - Saido, Takaomi C.

AU - Nakahata, Tatsutoshi

AU - Asada, Takashi

AU - Yamanaka, Shinya

AU - Iwata, Nobuhisa

AU - Inoue, Haruhisa

PY - 2011/9/30

Y1 - 2011/9/30

N2 - 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.

AB - 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.

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