Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness

Takayuki Kondo, Masashi Asai, Kayoko Tsukita, Yumiko Kutoku, Yutaka Ohsawa, Yoshihide Sunada, Keiko Imamura, Naohiro Egawa, Naoki Yahata, Keisuke Okita, Kazutoshi Takahashi, Isao Asaka, Takashi Aoi, Akira Watanabe, Kaori Watanabe, Chie Kadoya, Rie Nakano, Dai Watanabe, Kei Maruyama, Osamu HoriSatoshi Hibino, Tominari Choshi, Tatsutoshi Nakahata, Hiroyuki Hioki, Takeshi Kaneko, Motoko Naitoh, Katsuhiro Yoshikawa, Satoko Yamawaki, Shigehiko Suzuki, Ryuji Hata, Shu Ichi Ueno, Tsuneyoshi Seki, Kazuhiro Kobayashi, Tatsushi Toda, Kazuma Murakami, Kazuhiro Irie, William L. Klein, Hiroshi Mori, Takashi Asada, Ryosuke Takahashi, Nobuhisa Iwata, Shinya Yamanaka, Haruhisa Inoue

Research output: Contribution to journalArticle

401 Citations (Scopus)

Abstract

Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.

Original languageEnglish
Pages (from-to)487-496
Number of pages10
JournalCell Stem Cell
Volume12
Issue number4
DOIs
Publication statusPublished - 04-04-2013

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Induced Pluripotent Stem Cells
Docosahexaenoic Acids
Alzheimer Disease
Phenotype
Endoplasmic Reticulum Stress
Pharmaceutical Preparations
Amyloid beta-Protein Precursor
Amyloid
Astrocytes
Oxidative Stress
Neurons
Mutation
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Kondo, Takayuki ; Asai, Masashi ; Tsukita, Kayoko ; Kutoku, Yumiko ; Ohsawa, Yutaka ; Sunada, Yoshihide ; Imamura, Keiko ; Egawa, Naohiro ; Yahata, Naoki ; Okita, Keisuke ; Takahashi, Kazutoshi ; Asaka, Isao ; Aoi, Takashi ; Watanabe, Akira ; Watanabe, Kaori ; Kadoya, Chie ; Nakano, Rie ; Watanabe, Dai ; Maruyama, Kei ; Hori, Osamu ; Hibino, Satoshi ; Choshi, Tominari ; Nakahata, Tatsutoshi ; Hioki, Hiroyuki ; Kaneko, Takeshi ; Naitoh, Motoko ; Yoshikawa, Katsuhiro ; Yamawaki, Satoko ; Suzuki, Shigehiko ; Hata, Ryuji ; Ueno, Shu Ichi ; Seki, Tsuneyoshi ; Kobayashi, Kazuhiro ; Toda, Tatsushi ; Murakami, Kazuma ; Irie, Kazuhiro ; Klein, William L. ; Mori, Hiroshi ; Asada, Takashi ; Takahashi, Ryosuke ; Iwata, Nobuhisa ; Yamanaka, Shinya ; Inoue, Haruhisa. / Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. In: Cell Stem Cell. 2013 ; Vol. 12, No. 4. pp. 487-496.
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abstract = "Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.",
author = "Takayuki Kondo and Masashi Asai and Kayoko Tsukita and Yumiko Kutoku and Yutaka Ohsawa and Yoshihide Sunada and Keiko Imamura and Naohiro Egawa and Naoki Yahata and Keisuke Okita and Kazutoshi Takahashi and Isao Asaka and Takashi Aoi and Akira Watanabe and Kaori Watanabe and Chie Kadoya and Rie Nakano and Dai Watanabe and Kei Maruyama and Osamu Hori and Satoshi Hibino and Tominari Choshi and Tatsutoshi Nakahata and Hiroyuki Hioki and Takeshi Kaneko and Motoko Naitoh and Katsuhiro Yoshikawa and Satoko Yamawaki and Shigehiko Suzuki and Ryuji Hata and Ueno, {Shu Ichi} and Tsuneyoshi Seki and Kazuhiro Kobayashi and Tatsushi Toda and Kazuma Murakami and Kazuhiro Irie and Klein, {William L.} and Hiroshi Mori and Takashi Asada and Ryosuke Takahashi and Nobuhisa Iwata and Shinya Yamanaka and Haruhisa Inoue",
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Kondo, T, Asai, M, Tsukita, K, Kutoku, Y, Ohsawa, Y, Sunada, Y, Imamura, K, Egawa, N, Yahata, N, Okita, K, Takahashi, K, Asaka, I, Aoi, T, Watanabe, A, Watanabe, K, Kadoya, C, Nakano, R, Watanabe, D, Maruyama, K, Hori, O, Hibino, S, Choshi, T, Nakahata, T, Hioki, H, Kaneko, T, Naitoh, M, Yoshikawa, K, Yamawaki, S, Suzuki, S, Hata, R, Ueno, SI, Seki, T, Kobayashi, K, Toda, T, Murakami, K, Irie, K, Klein, WL, Mori, H, Asada, T, Takahashi, R, Iwata, N, Yamanaka, S & Inoue, H 2013, 'Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness', Cell Stem Cell, vol. 12, no. 4, pp. 487-496. https://doi.org/10.1016/j.stem.2013.01.009

Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. / Kondo, Takayuki; Asai, Masashi; Tsukita, Kayoko; Kutoku, Yumiko; Ohsawa, Yutaka; Sunada, Yoshihide; Imamura, Keiko; Egawa, Naohiro; Yahata, Naoki; Okita, Keisuke; Takahashi, Kazutoshi; Asaka, Isao; Aoi, Takashi; Watanabe, Akira; Watanabe, Kaori; Kadoya, Chie; Nakano, Rie; Watanabe, Dai; Maruyama, Kei; Hori, Osamu; Hibino, Satoshi; Choshi, Tominari; Nakahata, Tatsutoshi; Hioki, Hiroyuki; Kaneko, Takeshi; Naitoh, Motoko; Yoshikawa, Katsuhiro; Yamawaki, Satoko; Suzuki, Shigehiko; Hata, Ryuji; Ueno, Shu Ichi; Seki, Tsuneyoshi; Kobayashi, Kazuhiro; Toda, Tatsushi; Murakami, Kazuma; Irie, Kazuhiro; Klein, William L.; Mori, Hiroshi; Asada, Takashi; Takahashi, Ryosuke; Iwata, Nobuhisa; Yamanaka, Shinya; Inoue, Haruhisa.

In: Cell Stem Cell, Vol. 12, No. 4, 04.04.2013, p. 487-496.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness

AU - Kondo, Takayuki

AU - Asai, Masashi

AU - Tsukita, Kayoko

AU - Kutoku, Yumiko

AU - Ohsawa, Yutaka

AU - Sunada, Yoshihide

AU - Imamura, Keiko

AU - Egawa, Naohiro

AU - Yahata, Naoki

AU - Okita, Keisuke

AU - Takahashi, Kazutoshi

AU - Asaka, Isao

AU - Aoi, Takashi

AU - Watanabe, Akira

AU - Watanabe, Kaori

AU - Kadoya, Chie

AU - Nakano, Rie

AU - Watanabe, Dai

AU - Maruyama, Kei

AU - Hori, Osamu

AU - Hibino, Satoshi

AU - Choshi, Tominari

AU - Nakahata, Tatsutoshi

AU - Hioki, Hiroyuki

AU - Kaneko, Takeshi

AU - Naitoh, Motoko

AU - Yoshikawa, Katsuhiro

AU - Yamawaki, Satoko

AU - Suzuki, Shigehiko

AU - Hata, Ryuji

AU - Ueno, Shu Ichi

AU - Seki, Tsuneyoshi

AU - Kobayashi, Kazuhiro

AU - Toda, Tatsushi

AU - Murakami, Kazuma

AU - Irie, Kazuhiro

AU - Klein, William L.

AU - Mori, Hiroshi

AU - Asada, Takashi

AU - Takahashi, Ryosuke

AU - Iwata, Nobuhisa

AU - Yamanaka, Shinya

AU - Inoue, Haruhisa

PY - 2013/4/4

Y1 - 2013/4/4

N2 - Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.

AB - Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.

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