Alzheimer's disease (AD), a massive challenge to global health, is featured with the extracellular plaques made up of amyloid-β 42 (Aβ42) and the intracellular neurofibrillary pathology composed of the microtubule-associated protein tau. Women seem to have a higher vulnerability to AD. In the present study, we identified Thioredoxin-interacting protein (TXNIP) as a specifically highly-expressed gene in the hippocampus in female AD patients by bioinformatics analysis. Consistently, in the hippocampus in female AD mice, apoptosis and TXNIP expression were enhanced while TRX expression was suppressed. In Aβ42-stimulated SH-SY5Y cells, the administration of estradiol significantly rescued Aβ42-suppressed cell viability and protein level of TRX while inhibited Aβ42-induced increases in ROS production, cell apoptosis, ΔΨm, and the protein levels of PERK, IREα, and TXNIP, further confirming the potential role of estrogen in AD progression and the involvement of TXNIP/TRX axis. Furthermore, the protective effects of estradiol against Aβ42-induced in vitro neurotoxicity on SH-SY5Y cells could be significantly reversed by AMPK inhibitor, Compound C, indicating that estradiol could improve Aβ42-induced AD via TXNIP/TRX and AMPK signaling. In summary, we demonstrated the cellular function of estradiol on Aβ42-induced in vitro neurotoxicity on SH-SY5Y cells and a novel mechanism of TXNIP/TRX axis involved in estradiol function via AMPK signaling.

中文翻译：

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雌激素通过TXNIP / TRX轴和AMPK信号传导保护神经母细胞瘤细胞免受淀粉样β-42（Aβ42）诱导的凋亡。

阿尔茨海默氏病（AD）是对全球健康的巨大挑战，其特征在于由β-淀粉样蛋白42（Aβ42）组成的细胞外斑块和由微管相关蛋白tau组成的细胞内神经原纤维病理。妇女似乎更容易患AD。在本研究中，我们通过生物信息学分析确定了硫氧还蛋白相互作用蛋白（TXNIP）是女性AD患者海马中特异表达的基因。一致地，在雌性AD小鼠的海马中，凋亡和TXNIP表达增强，而TRX表达被抑制。在Aβ42刺激的SH-SY5Y细胞中，雌二醇的给药可显着挽救Aβ42抑制的TRX的细胞活力和蛋白质水平，同时抑制Aβ42诱导的ROS产生，细胞凋亡，ΔΨm，以及PERK，IREα和TXNIP的蛋白质水平，进一步证实了雌激素在AD进展中的潜在作用以及TXNIP / TRX轴的参与。此外，AMPK抑制剂化合物C可明显逆转雌二醇对Aβ42诱导的SH-SY5Y细胞体外神经毒性的保护作用，表明雌二醇可通过TXNIP / TRX和AMPK信号转导改善Aβ42诱导的AD。总之，我们证明了雌二醇对Aβ42诱导的SH-SY5Y细胞体外神经毒性的细胞功能，以及通过AMPK信号传导参与雌二醇功能的TXNIP / TRX轴的新机制。AMPK抑制剂化合物C可明显逆转雌二醇对Aβ42诱导的SH-SY5Y细胞神经毒性的保护作用，表明雌二醇可通过TXNIP / TRX和AMPK信号转导改善Aβ42诱导的AD。总之，我们证明了雌二醇对Aβ42诱导的SH-SY5Y细胞体外神经毒性的细胞功能，以及通过AMPK信号传导参与雌二醇功能的TXNIP / TRX轴的新机制。AMPK抑制剂化合物C可明显逆转雌二醇对Aβ42诱导的SH-SY5Y细胞神经毒性的保护作用，表明雌二醇可通过TXNIP / TRX和AMPK信号转导改善Aβ42诱导的AD。总之，我们证明了雌二醇对Aβ42诱导的SH-SY5Y细胞体外神经毒性的细胞功能，以及通过AMPK信号传导参与雌二醇功能的TXNIP / TRX轴的新机制。