The cell-type-specific response of neural cells to oxidative stress, a crucial mechanism for accelerating aging and cognitive dysfunction in Alzheimer's disease (AD), is still far from understood. Here, we employed human-induced pluripotent stem cells (hiPSCs)-derived neural stem cells (hiPSC-NSCs), neurons (hiPSC-Neurons), and microglia-like cells (hiPSC-MGLs) from sporadic AD (sAD) patients, age-matched cognitive normal controls (CNCs), and young subjects to observe human neural cell-type response to H₂O₂ stimulation. Without H₂O₂ exposure, reactive oxygen species (ROS) cannot be detected in hiPSC-NSCs from all three groups, but the viability of hiPSC-NSCs from AD patients was significantly lower than those of CNCs and young subjects. There were no significant differences in ROS, viabilities, neurite length, and neurite branch points in hiPSC-Neurons among three groups. No significant differences in viabilities, phagocytosis, and secretion of cytokines were observed in hiPSC-MGLs among three groups, but higher ROS levels in sAD hiPSC-MGLs. Under H₂O₂ exposure, the viability, neurite length, and neurite branch points of hiPSC-Neurons from AD patients reduced more significantly accompanied by more ROS release. H₂O₂ exposure caused hiPSC-MGLs from AD patients to release more ROS, cytokines, and stronger phagocytosis. Nevertheless, H₂O₂ exposure had no effect on viability of hiPSC-NSCs. Our results showed hiPSC-Neurons and hiPSC-MGLs were more sensitive to H₂O₂ than hiPSC-NSCs, which indicated the different response styles of hiPSC-NSCs, hiPSC-Neurons, and hiPSC-MGLs to oxidative stress. HiPSC-derived neural cells from AD patients suffered more severe injury from H₂O₂ than those of CNCs and young subjects, indicating that the vulnerability to oxidative stress of AD patients can be recapitulated in hiPSCs.

中文翻译：

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来自阿尔茨海默病患者的人类诱导多能干细胞衍生神经细胞对氧化应激表现出不同的敏感性

神经细胞对氧化应激的细胞类型特异性反应，这是加速阿尔茨海默病 (AD) 衰老和认知功能障碍的关键机制，但仍远未了解。在这里，我们采用了来自散发性 AD (sAD) 患者、年龄-匹配的认知正常对照 (CNC) 和年轻受试者观察人类神经细胞类型对 H ₂ O ₂刺激的反应。不含 H ₂ O ₂暴露后，在所有三组的 hiPSC-NSCs 中都无法检测到活性氧 (ROS)，但 AD 患者的 hiPSC-NSCs 的活力显着低于 CNCs 和年轻受试者。三组 hiPSC-Neurons 的 ROS、活力、轴突长度和轴突分支点均无显着差异。在 hiPSC-MGLs 中，三组中未观察到活力、吞噬作用和细胞因子分泌的显着差异，但 sAD hiPSC-MGLs 中的 ROS 水平较高。在H ₂ O ₂暴露下，来自AD患者的hiPSC-Neurons的活力、神经突长度和神经突分支点降低更显着​​，伴随着更多的ROS释放。H ₂ O ₂暴露导致 AD 患者的 hiPSC-MGLs 释放更多的 ROS、细胞因子和更强的吞噬作用。然而，H ₂ O ₂暴露对hiPSC-NSCs的活力没有影响。我们的结果表明，hiPSC-Neurons 和 hiPSC-MGLs 对 H ₂ O ₂比 hiPSC-NSCs更敏感，这表明 hiPSC-NSCs、hiPSC-Neurons 和 hiPSC-MGLs 对氧化应激的反应方式不同。来自 AD 患者的 HiPSC 衍生神经细胞遭受的 H ₂ O ₂比 CNC 和年轻受试者更严重，表明 AD 患者对氧化应激的脆弱性可以在 hiPSC 中重现。