Modeling Alzheimer¡¯s Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular A¦Â and Differential Drug Responsiveness

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• 作者：Takayuki Kondo¹ ; ² ; ⁷ ; Masashi Asai⁷ ; ⁹ ; ¹⁰ ; Kayoko Tsukita¹ ; ⁷ ; Yumiko Kutoku¹¹ ; Yutaka Ohsawa¹¹ ; Yoshihide Sunada¹¹ ; Keiko Imamura¹ ; Naohiro Egawa¹ ; Naoki Yahata¹ ; ⁷ ; Keisuke Okita¹ ; Kazutoshi Takahashi¹ ; Isao Asaka¹ ; Takashi Aoi¹ ; Akira Watanabe¹ ; Kaori Watanabe⁷ ; ¹⁰ ; Chie Kadoya⁷ ; ¹⁰ ; Rie Nakano⁷ ; ¹⁰ ; Dai Watanabe³ ; Kei Maruyama⁹ ; Osamu Hori¹² ; Satoshi Hibino¹³ ; Tominari Choshi¹³ ; Tatsutoshi Nakahata¹ ; Hiroyuki Hioki⁴ ; Takeshi Kaneko⁴ ; Motoko Naitoh⁵ ; Katsuhiro Yoshikawa⁵ ; Satoko Yamawaki⁵ ; Shigehiko Suzuki⁵ ; Ryuji Hata¹⁴ ; Shu-ichi Ueno¹⁵ ; Tsuneyoshi Seki¹⁶ ; Kazuhiro Kobayashi¹⁶ ; Tatsushi Toda¹⁶ ; Kazuma Murakami⁶ ; Kazuhiro Irie⁶ ; William L. Klein¹⁷ ; Hiroshi Mori¹⁸ ; Takashi Asada¹⁹ ; Ryosuke Takahashi² ; Nobuhisa Iwata⁷ ; ¹⁰ ; ^{iwata-n@nagasaki-u.ac.jp} ; Shinya Yamanaka¹ ; ⁸ ; Haruhisa Inoue¹ ; ⁷ ; ⁸ ; ^{haruhisa@cira.kyoto-u.ac.jp}
• 刊名：Cell Stem Cell
• 出版年：2013
• 出版时间：4 April, 2013
• 年：2013
• 卷：12
• 期：4
• 页码：487-496
• 全文大小：2180 K

文摘

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Summary

Oligomeric forms of amyloid-¦Â peptide (A¦Â) 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. A¦Â oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693¦¤ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated A¦Â 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.