title: Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease.
abstract: The secretion of proteins that lack a signal sequence to the extracellular milieu is regulated by their transition through the unconventional secretory pathway. IDE (insulin-degrading enzyme) is one of the major proteases of amyloid beta peptide (Aβ), a presumed causative molecule in Alzheimer disease (AD) pathogenesis. IDE acts in the extracellular space despite having no signal sequence, but the underlying mechanism of IDE secretion extracellularly is still unknown. In this study, we found that IDE levels were reduced in the cerebrospinal fluid (CSF) of patients with AD and in pathology-bearing AD-model mice. Since astrocytes are the main cell types for IDE secretion, astrocytes were treated with Aβ. Aβ increased the IDE levels in a time- and concentration-dependent manner. Moreover, IDE secretion was associated with an autophagy-based unconventional secretory pathway, and depended on the activity of RAB8A and GORASP (Golgi reassembly stacking protein). Finally, mice with global haploinsufficiency of an essential autophagy gene, showed decreased IDE levels in the CSF in response to an intracerebroventricular (i.c.v.) injection of Aβ. These results indicate that IDE is secreted from astrocytes through an autophagy-based unconventional secretory pathway in AD conditions, and that the regulation of autophagy is a potential therapeutic target in addressing Aβ pathology.
authors.affiliation: a Department of Biochemistry & Biomedical Sciences , Seoul National University College of Medicine , Seoul , Korea.|b Neuroscience Research Institute, Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Son
authors.affiliation: a Department of Biochemistry & Biomedical Sciences , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Moon-Yong
authors.initials: MY
authors.lastname: Cha
authors.affiliation: a Department of Biochemistry & Biomedical Sciences , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Heesun
authors.initials: H
authors.lastname: Choi
authors.affiliation: a Department of Biochemistry & Biomedical Sciences , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Seokjo
authors.initials: S
authors.lastname: Kang
authors.affiliation: a Department of Biochemistry & Biomedical Sciences , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Choi
authors.affiliation: c Department of Medicine , Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , Korea.
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.affiliation: d Department of Neurology , Soonchunhyang University Bucheon Hospital , Bucheon , Korea.
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Park
authors.affiliation: a Department of Biochemistry & Biomedical Sciences , Seoul National University College of Medicine , Seoul , Korea.|b Neuroscience Research Institute, Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D055571:Secretory Pathway / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D007328:Insulin
keywords: Alzheimer disease; amyloid beta; autophagy; autophagy-based unconventional secretion; insulin-degrading enzyme