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
N1 - Funding Information:
We observed that the accumulation of Aβ oligomers induced ER and oxidative stress both in AD(APP-E693Δ) and in sporadic AD(AD8K213) neurons, although caspase-4 activation appeared not to accompany sporadic AD, probably because of the lesser extent of ER stress in comparison to AD(APP-E693Δ). Previously, Nishitsuji et al. (2009) reported that accumulated Aβ oligomers in ER provoke ER stress. This result suggests that oligomers represent a self-aggregating state of Aβ. During this process, Aβ generates ROS, which is supported by the fact that Aβ coordinates the metal ions zinc, iron, and copper, which induce the oligomerization of Aβ. Iron and copper then cause the generation of toxic ROS and calcium dysregulation ( Barnham et al., 2004 ), leading to membrane lipid peroxidation and the impairment of the function of a range of membrane-associated proteins ( Hensley et al., 1994 ; Butterfield, 2003 ), antioxidant factors being thought to protect ER-stress-induced cellular toxicities ( Malhotra and Kaufman, 2007 ).
Funding Information:
We would like to express our sincere gratitude to all our coworkers and collaborators, Mari Ohnuki, Megumi Kumazaki, Mitsuyo Kawada, Fumihiko Adachi, Takako Enami, and Misato Funayama for technical assistance; Nobuya Inagaki and Norio Harada for technical advice; and Kazumi Murai for editing the manuscript. This research was funded in part by a grant from the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) of the Japan Society for the Promotion of Science (JSPS) to S.Y., from the Alzheimer’s Association (IIRG-09-132098) to H.M., from the JST Yamanaka iPS Cell Special Project to S.Y. and H.I., from CREST to H.I., H.M., N.I., and T.T., from a Grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan to H.I., from a Grant-in-Aid for Scientific Research on Innovative Area “Foundation of Synapse and Neurocircuit Pathology” (22110007) from the Ministry of Education, Culture, Sports, Science and Technology of Japan to H.I. and N.I., and from the Japan Research Foundation for Clinical Pharmacology to H.I. H.I. conceived the project; T.K., N.I., M.A., and H.I. designed the experiments; T.K., N.I., M.A., K.W., C.K., R.N., N.E., N.Y. and K. Tsukita performed the experiments; T.K., N.I., M.A., and H.I. analyzed the data; K.O., I.A., K.M., T.N., K.I., W.L.K., O.H., S.H., and T.C. contributed reagents, materials and analysis tools; Y.K., Y.O., Y.S., M.N., K.Y., S.Y., S.S., T.A., R.H., and S.U. recruited the patients; R.T., H.M., and S.Y. provided critical reading and scientific discussions; T.S., K.K., T.T., and K. Takahashi performed microarray analysis; T.A. performed karyotyping; A.W. performed bisulfite genomic sequencing; K.I. and D.W. performed electrophysiology; K. Tsukita, T.K., and H.H. produced the lentivirus; H.I., N.I., M.A., and T.K. wrote the paper. The experimental protocols dealing with human or animal subjects were approved by the institutional review board at each institute. S.Y. is a member without salary of the scientific advisory boards of iPierian, iPS Academia Japan, Megakaryon Corporation, and Retina Institute Japan.
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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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 -