Amyloid β (Aβ) is a peptide fragment of the amyloid precursor protein that triggers the progression of Alzheimer’s Disease (AD). It is believed that Aβ contributes to neurodegeneration in several ways, including mitochondria dysfunction, oxidative stress and brain insulin resistance. Therefore, protecting neurons from Aβ-induced neurotoxicity is an effective strategy for attenuating AD pathogenesis. Recently, applications of stem cell-based therapies have demonstrated the ability to reduce the progression and outcome of neurodegenerative diseases. Particularly, Nanog is recognized as a stem cell-related pluripotency factor that enhances self-renewing capacities and helps reduce the senescent phenotypes of aged neuronal cells. However, whether the upregulation of Nanog can be an effective approach to alleviate Aβ-induced neurotoxicity and senescence is not yet understood. In the present study, we transiently overexpressed Nanog—both in vitro and in vivo—and investigated the protective effects and underlying mechanisms against Aβ. We found that overexpression of Nanog is responsible for attenuating Aβ-triggered neuronal insulin resistance, which restores cell survival through reducing intracellular mitochondrial superoxide accumulation and cellular senescence. In addition, upregulation of Nanog expression appears to increase secretion of neurotrophic factors through activation of the Nrf2 antioxidant defense pathway. Furthermore, improvement of memory and learning were also observed in rat model of Aβ neurotoxicity mediated by upregulation of Nanog in the brain. Taken together, our study suggests a potential role for Nanog in attenuating the neurotoxic effects of Aβ, which in turn, suggests that strategies to enhance Nanog expression may be used as a novel intervention for reducing Aβ neurotoxicity in the AD brain.

中文翻译：

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多能性因子Nanog通过胰岛素敏感性恢复保护神经元β淀粉样蛋白诱导的毒性和氧化应激。

淀粉样蛋白β（Aβ）是淀粉样蛋白前体蛋白的肽片段，可触发阿尔茨海默氏病（AD）的发展。相信Aβ以多种方式促进神经变性，包括线粒体功能障碍，氧化应激和脑胰岛素抵抗。因此，保护​​神经元免受Aβ诱导的神经毒性是减轻AD发病机理的有效策略。最近，基于干细胞疗法的应用已证明能够减少神经退行性疾病的进展和结果。特别地，Nanog被认为是干细胞相关的多能性因子，可增强自我更新的能力并有助于减少衰老的神经元细胞的衰老表型。然而，Nanog的上调是否可以减轻Aβ诱导的神经毒性和衰老的有效方法尚不清楚。在本研究中，我们在体外和体内都短暂表达了Nanog，并研究了其对Aβ的保护作用及其潜在机制。我们发现，Nanog的过度表达是导致Aβ触发的神经元胰岛素抵抗减弱的原因，它通过减少细胞内线粒体超氧化物的积累和细胞衰老来恢复细胞存活。此外，Nanog表达的上调似乎通过激活Nrf2抗氧化剂防御途径来增加神经营养因子的分泌。此外，在由脑中Nanog的上调介导的Aβ神经毒性的大鼠模型中也观察到记忆和学习的改善。在一起