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

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Authors
Son, Sung Min; Kang, Seokjo; Choi, Heesun; Mook-Jung, Inhee
Issue Date
2015-10-31
Publisher
BioMed Central
Citation
Molecular Neurodegeneration, 10(1):56
Keywords
StatinInsulin-degrading enzyme (IDE)Autophagy-based unconventional secretionAmyloid-β (Aβ)Alzheimer’s disease (AD)
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.
Language
English
URI
http://hdl.handle.net/10371/109841
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biochemistry & Molecular Biology (생화학교실)Journal Papers (저널논문_생화학교실)
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