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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。

Statins induce insulin-degrading enzyme secretion from astrocytes via an autophagy-based unconventional secretory pathway.

作者信息

Son Sung Min, Kang Seokjo, Choi Heesun, Mook-Jung Inhee

机构信息

Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, Korea.

Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea.

出版信息

Mol Neurodegener. 2015 Oct 31;10:56. doi: 10.1186/s13024-015-0054-3.

DOI:10.1186/s13024-015-0054-3
PMID:26520569
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4628355/
Abstract

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.

摘要

背景

胰岛素降解酶（IDE）是淀粉样β肽（Aβ）的主要蛋白酶，Aβ是阿尔茨海默病（AD）发病机制中一种突出的毒性蛋白。先前的研究表明他汀类药物可促进IDE分泌；然而，其潜在机制尚不清楚，因为IDE没有信号序列。

结果

在本研究中，我们发现辛伐他汀（0.2 μM，作用12小时）可诱导细胞外Aβ40降解，这依赖于原代星形胶质细胞分泌的IDE。此外，辛伐他汀以时间和剂量依赖的方式增加星形胶质细胞中IDE的分泌。而且，辛伐他汀介导的IDE分泌是由基于自噬的非传统分泌途径介导的，自噬通量调节辛伐他汀介导的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星形胶质细胞分泌IDE的新途径。调节该途径可能通过增强Aβ的细胞外清除为治疗Aβ病理提供潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/354ed015967d/13024_2015_54_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/c78153ab516c/13024_2015_54_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/8ee56b87acb9/13024_2015_54_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/b6e0aae365d3/13024_2015_54_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/8f576d95ba22/13024_2015_54_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/72564ff58117/13024_2015_54_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/354ed015967d/13024_2015_54_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/c78153ab516c/13024_2015_54_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/8ee56b87acb9/13024_2015_54_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/b6e0aae365d3/13024_2015_54_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/8f576d95ba22/13024_2015_54_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/72564ff58117/13024_2015_54_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09e9/4628355/354ed015967d/13024_2015_54_Fig6_HTML.jpg

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