BACKGROUND Insulin degrading enzyme (IDE) is a major protease of amyloid beta peptide (Aβ), a prominent toxic protein in Alzheimer's disease (AD) pathogenesis. Previous studies suggested that statins promote IDE secretion; however, the underlying mechanism is unknown, as IDE has no signal sequence. RESULTS In this study, we found that simvastatin (0.2 μM for 12 h) induced the degradation of extracellular Aβ40, which depended on IDE secretion from primary astrocytes. In addition, simvastatin increased IDE secretion from astrocytes in a time- and dose-dependent manner. Moreover, simvastatin-mediated IDE secretion was mediated by an autophagy-based unconventional secretory pathway, and autophagic flux regulated simvastatin-mediated IDE secretion. Finally, simvastatin activated autophagy via the LKB1-AMPK-mTOR signaling pathway in astrocytes. CONCLUSIONS These results demonstrate a novel pathway for statin-mediated IDE secretion from astrocytes. Modulation of this pathway could provide a potential therapeutic target for treatment of Aβ pathology by enhancing extracellular clearance of Aβ.

中文翻译：

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他汀类药物通过基于自噬的非常规分泌途径诱导星形胶质细胞分泌胰岛素降解酶。

背景技术胰岛素降解酶（IDE）是淀粉样β肽（Aβ）的主要蛋白酶，淀粉样β肽是阿尔茨海默氏病（AD）发病机理中的突出毒性蛋白。先前的研究表明，他汀类药物可促进IDE分泌。但是，底层机制尚不明确，因为IDE没有信号序列。结果在这项研究中，我们发现辛伐他汀（0.2μM，持续12 h）诱导了细胞外Aβ40的降解，这取决于原代星形胶质细胞的IDE分泌。此外，辛伐他汀以时间和剂量依赖性方式增加星形胶质细胞的IDE分泌。此外，辛伐他汀介导的IDE分泌是通过基于自噬的非常规分泌途径介导的，而自噬通量调节了辛伐他汀介导的IDE分泌。最后，辛伐他汀通过星形胶质细胞中的LKB1-AMPK-mTOR信号通路激活自噬。结论这些结果证明了他汀类药物介导的星形胶质细胞分泌IDE的新途径。该途径的调节可通过增强Aβ的细胞外清除率而为Aβ病理学的治疗提供潜在的治疗靶标。