Department of Pharmacy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
Int Immunopharmacol. 2018 Jan;54:336-343. doi: 10.1016/j.intimp.2017.11.044. Epub 2017 Dec 1.
Autophagy is an intracellular catabolic mechanism essential for recycling intracellular unfolding protein and eliminating toxic protein aggregates. Several studies have shown that deficient autophagy is implicated in the development of Alzheimer's disease (AD) progression. To date, rapidly emerging evidence suggests that neurosteroid progesterone (PG) may play an important role in ameliorating AD. However, the role of PG and its neuroprotective mechanism in regulating autophagy still require further investigation. Here, we investigated the protective effects of PG against Aβ-induced inflammatory responses in astrocytes and its underlying mechanism in mediating autophagy. Remarkably, Aβ induced astrocyte dysfunction in autophagic activation and up-regulated inflammatory secretion. However, the autophagy inducer rapamycin (RAPA) significantly suppressed Aβ-induced inflammation in astrocytes. In astrocytes, treatment with Aβ caused autophagy deficiency, whereas PG significantly increased autophagy activation. Finally, PG suppressed Aβ-induced neuroinflammatory production via enhancing autophagy together with regulating mTOR signaling. Taken together, these results show that autophagy is a vital mechanism against Aβ-induced neuroinflammatory responses in astrocytes and demonstrate the potential neuroprotective mechanism of PG in suppressing neuroinflammatory responses by enhancing autophagy. Therefore, uncovering the neuroprotective mechanism of PG may provide new insight into novel therapies for the amelioration of AD.
自噬是一种重要的细胞内分解代谢机制，对于回收细胞内展开的蛋白质和消除有毒的蛋白质聚集体至关重要。有几项研究表明，自噬不足与阿尔茨海默病（AD）的发展有关。迄今为止，迅速涌现的证据表明，神经甾体孕酮（PG）可能在改善 AD 方面发挥重要作用。然而，PG 的作用及其在调节自噬方面的神经保护机制仍需要进一步研究。在这里，我们研究了 PG 对 Aβ诱导的星形胶质细胞炎症反应的保护作用及其在调节自噬中的潜在机制。值得注意的是，Aβ诱导星形胶质细胞自噬激活障碍和炎症分泌上调。然而，自噬诱导剂雷帕霉素（RAPA）可显著抑制 Aβ诱导的星形胶质细胞炎症。在星形胶质细胞中，Aβ处理导致自噬缺陷，而 PG 显著增加自噬激活。最后，PG 通过增强自噬和调节 mTOR 信号通路来抑制 Aβ诱导的神经炎症产物的产生。总之，这些结果表明，自噬是星形胶质细胞中 Aβ诱导的神经炎症反应的重要机制，并证明了 PG 通过增强自噬来抑制神经炎症反应的潜在神经保护机制。因此，揭示 PG 的神经保护机制可能为改善 AD 的新疗法提供新的思路。
