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

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

Author information

1
Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, Korea. sonsm119@snu.ac.kr.
2
Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea. sonsm119@snu.ac.kr.
3
Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, Korea. sjkang0420@snu.ac.kr.
4
Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, Korea. sujup@snu.ac.kr.
5
Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, Korea. inhee@snu.ac.kr.
6
Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea. inhee@snu.ac.kr.

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.

PMID:
26520569
PMCID:
PMC4628355
DOI:
10.1186/s13024-015-0054-3
[Indexed for MEDLINE]
Free PMC Article

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