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 language | English |
|---|---|
| Pages (from-to) | 487-496 |
| Number of pages | 10 |
| Journal | Cell Stem Cell |
| Volume | 12 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 04-04-2013 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Genetics
- Cell Biology
Cite this
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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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=84875916922&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875916922&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2013.01.009
DO - 10.1016/j.stem.2013.01.009
M3 - Article
C2 - 23434393
AN - SCOPUS:84875916922
VL - 12
SP - 487
EP - 496
JO - Cell Stem Cell
JF - Cell Stem Cell
SN - 1934-5909
IS - 4
ER -