title: Statins induce insulin-degrading enzyme secretion from astrocytes via an autophagy-based unconventional secretory pathway.
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.
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, Korea. sonsm119@snu.ac.kr.|Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea. sonsm119@snu.ac.kr.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Son
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, Korea. sjkang0420@snu.ac.kr.
authors.forename: Seokjo
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, Korea. sujup@snu.ac.kr.
authors.forename: Heesun
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biochemistry & Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 110-799, Korea. inhee@snu.ac.kr.|Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea. inhee@snu.ac.kr.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D007339:Insulysin / Q000378:metabolism*; D051379:Mice; D055571:Secretory Pathway; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D019821:Simvastatin; D007339:Insulysin