Alzheimer’s disease (AD) is a neurodegenerative disorder caused by amyloid beta oligomers (AβO), which induce cell death by triggering oxidative stress and endoplasmic reticulum (ER) stress. Oxidative stress is regulated by antioxidant enzymes, including peroxiredoxins. Peroxiredoxins (Prx) are classified into six subtypes, based on their localization and cysteine residues, and protect cells by scavenging hydrogen peroxide (H₂O₂). Peroxiredoxin 4 (Prx4) is unique in being localized to the ER; however, whether Prx4 protects neuronal cells from AβO-induced toxicity remains unclear, although Prx4 expression is upregulated in AβO-induced oxidative stress and ER stress. In this study, we established HT-22 cells in which Prx4 was either overexpressed or silenced to investigate its role in AβO-induced toxicity. AβO-stimulation of HT-22 cells with overexpressed Prx4 caused decreases in both AβO-induced ROS and ER stress (followed by ER expansion). In contrast, AβO stimulation caused increases in both ROS and ER stress that were notably higher in HT-22 cells with silenced Prx4 expression than in HT-22 cells. Consequently, Prx4 overexpression decreased apoptotic cell death and ameliorated the AβO-induced increase in intracellular Ca²⁺. Therefore, we conclude that Prx4 has a protective effect against AβO-mediated oxidative stress, ER stress, and neuronal cell death. Furthermore, these results suggest that Prx4 may be a target for preventing AβO toxicity in AD.

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中文翻译：

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Peroxiredoxin 4通过抑制HT-22海马神经元细胞的内质网应激，改善了淀粉样β低聚物介导的细胞凋亡。

阿尔茨海默氏病（AD）是由淀粉样蛋白β寡聚物（AβO）引起的神经退行性疾病，它通过触发氧化应激和内质网（ER）应激来诱导细胞死亡。氧化应激由抗氧化剂酶（包括过氧化物酶）调节。过氧化物酶（Prx）根据其定位和半胱氨酸残基分为六种亚型，并通过清除过氧化氢（H ₂ O ₂）。Peroxiredoxin 4（Prx4）在ER内具有独特性。然而，尽管在AβO诱导的氧化应激和ER应激中Prx4表达上调，但Prx4是否能保护神经元细胞免受AβO诱导的毒性影响。在这项研究中，我们建立了HT-22细胞，其中Prx4过表达或沉默，以研究其在AβO诱导的毒性中的作用。Prx4过度表达对HT-22细胞的AβO刺激引起AβO诱导的ROS和ER应激均降低（随后为ER扩展）。相比之下，AβO刺激引起ROS和ER应激的增加，在沉默的Prx4表达的HT-22细胞中，其显着高于HT-22细胞。因此，Prx4过表达减少了凋亡细胞死亡并改善了AβO诱导的细胞内Ca ^2+的增加。因此，我们得出结论，Prx4对AβO介导的氧化应激，ER应激和神经元细胞死亡具有保护作用。此外，这些结果表明Prx4可能是预防AD中AβO毒性的靶标。

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