Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress. Here, we show that inflammatory stimulation leads to metabolic activation of human astrocytes and reduces amyloid secretion. On the other hand, the activation of oxidative metabolism leads to increased reactive oxygen species production especially in AD astrocytes. While healthy astrocytes increase glutathione (GSH) release to protect the cells, Presenilin-1-mutated AD patient astrocytes do not. Thus, chronic inflammation is likely to induce oxidative damage in AD astrocytes. Activation of NRF2, the major regulator of cellular antioxidant defenses, encoded by the NFE2L2 gene, poses several beneficial effects on AD astrocytes. We report here that the activation of NRF2 pathway reduces amyloid secretion, normalizes cytokine release, and increases GSH secretion in AD astrocytes. NRF2 induction also activates the metabolism of astrocytes and increases the utilization of glycolysis. Taken together, targeting NRF2 in astrocytes could be a potent therapeutic strategy in AD.

中文翻译：

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NF-E2 相关因子 2 激活可增强人类 Presenilin-1 突变阿尔茨海默病星形胶质细胞的抗氧化防御并改善炎症和淀粉样蛋白特性。


阿尔茨海默病 (AD) 是一种常见的痴呆症，影响大量人群并严重损害生活质量。尽管对动物模型进行了广泛的研究和大量有希望的治疗试验，但仍然没有针对 AD 的治愈方法。星形胶质细胞是中枢神经系统最常见的细胞类型，已被证明在主要 AD 病理学中发挥作用，包括淀粉样斑块的积累、神经炎症和氧化应激。在这里，我们发现炎症刺激会导致人类星形胶质细胞的代谢激活并减少淀粉样蛋白的分泌。另一方面，氧化代谢的激活导致活性氧产生增加，尤其是在 AD 星形胶质细胞中。虽然健康的星形胶质细胞会增加谷胱甘肽 (GSH) 的释放来保护细胞，但 Presenilin-1 突变的 AD 患者星形胶质细胞却不会。因此，慢性炎症可能会诱发 AD 星形胶质细胞的氧化损伤。 NRF2 是细胞抗氧化防御的主要调节因子，由 NFE2L2 基因编码，其激活对 AD 星形胶质细胞产生多种有益影响。我们在此报告，NRF2 通路的激活减少了 AD 星形胶质细胞中淀粉样蛋白的分泌，使细胞因子的释放正常化，并增加了 GSH 的分泌。 NRF2 诱导还激活星形胶质细胞的新陈代谢并增加糖酵解的利用率。总而言之，靶向星形胶质细胞中的 NRF2 可能是 AD 的有效治疗策略。