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Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease.

Authors: Son, Sung Min  Cha, Moon-Yong  Choi, Heesun  Kang, Seokjo  Choi, Hyunjung  Lee, Myung-Shik  Park, Sun Ah  Mook-Jung, Inhee 
Citation: Son SM, etal., Autophagy. 2016 May 3;12(5):784-800. doi: 10.1080/15548627.2016.1159375. Epub 2016 Mar 10.
Pubmed: (View Article at PubMed) PMID:26963025
DOI: Full-text: DOI:10.1080/15548627.2016.1159375

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 (Aß), 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 Aß. Aß 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 Aß. 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 Aß pathology.


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RGD ID: 13792798
Created: 2018-09-28
Species: All species
Last Modified: 2018-09-28
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.