Modeling Alzheimer’s Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular Aβ and Differential Drug Responsiveness

• DOI: 10.1016/j.stem.2013.01.009
• Publication Date: 2013-02-21T19:50:03Z
• Authors: 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 Hori; Satoshi 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
• Keywords: Cerebral Cortex; Neurons; 0303 health sciences; Amyloid beta-Peptides; Docosahexaenoic Acids; Induced Pluripotent Stem Cells; Intracellular Space; Cell Differentiation; Cell Biology; Models, Biological; 3. Good health; Oxidative Stress; 03 medical and health sciences; Phenotype; Alzheimer Disease; Genetics; Molecular Medicine; Humans; Mutant Proteins; Protein Structure, Quaternary

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.