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

• Published in: Cell stem cell 2013-04, Vol.12 (4), p.487-496
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - pathology; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Cell Differentiation; Cerebral Cortex - pathology; Docosahexaenoic Acids - pharmacology; Humans; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Intracellular Space - drug effects; Intracellular Space - metabolism; Models, Biological; Mutant Proteins; Neurons - metabolism; Neurons - pathology; Oxidative Stress - drug effects; Phenotype; Protein Structure, Quaternary
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2013.01.009

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. [Display omitted] ► Familial and sporadic Alzheimer’s patient iPSC-derived neural cells were analyzed ► Intracellular Aβ oligomers accumulate in lines from some patients ► Aβ oligomer accumulation is associated with ER and oxidative stress ► DHA-alleviated ER and oxidative stresses improve cell viability iPSC-derived neural cells from Alzheimer’s patients highlight accumulation of the intracellular amyloid β peptide and cellular stress. Differential responsiveness to DHA may help explain the variation seen in the clinical efficacy of this drug.