Modeling Alzheimer's Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular Aβ and Differential Drug Responsiveness
Modeling Alzheimer's Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular Aβ and Differential Drug Responsiveness
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DOI：
10.1016/j.stem.2013.01.009
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发表时间：
2013-04-04
期刊：
影响因子：
23.9
通讯作者：
Inoue, Haruhisa
中科院分区：
文献类型：
--
作者：
Kondo, Takayuki;Asai, Masashi;Inoue, Haruhisa
淀粉样β肽（A β）的寡聚体形式被认为在阿尔茨海默病（AD）的发病机制中起关键作用，但其机制仍不清楚。在这里，我们从家族性和散发性AD患者中产生了诱导多能干细胞（iPSC），并将其分化为神经细胞。A β寡聚体在来自具有家族性淀粉样前体蛋白（APP）-E693 Delta突变和散发性AD的患者的细胞中的iPSC衍生的神经元和星形胶质细胞中积累，导致内质网（ER）和氧化应激。积累的A β低聚物不具有蛋白水解抗性，二十二碳六烯酸（DHA）处理缓解了AD神经细胞的应激反应。ER应激和DHA反应性的不同表现可能有助于解释使用DHA治疗获得的不同临床结果，并表明DHA实际上可能对一部分患者有效。它还说明了患者特异性iPSC如何用于分析AD发病机制和评估药物。
Oligomeric forms of amyloid-beta peptide (A beta) 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 beta oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693 Delta mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated A beta 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.