Document Detail

Variations in the effects on synthesis of amyloid beta protein in modulated autophagic conditions.
MedLine Citation:
PMID:  19215663     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Autophagy, the intracellular breakdown system for proteins and some organelles, is considered to be important in neurodegenerative disease. Recent reports suggest that autophagy plays an important role in Alzheimer's disease pathogenesis and autophagic vacuoles (AVs) may be sites of amyloid beta protein (Abeta) generation. We attempted to determine if imposed changes in autophagic activity are linked to Abeta generation and secretion in cultured cells. METHODS: We used Chinese hamster ovary cells, stably expressing wild-type APP 751. We treated the cells with three known autophagy modulating conditions, rapamycin treatment, U18666A treatment and cholesterol depletion. RESULTS: All the three conditions resulted in increased levels of LC3-II by western blotting, together with an increase in the number of LC3-positive granules. However, the effects on Abeta production were inconsistent. The rapamycin treatment increased Abeta production and secretion, but the other two conditions had opposite effects. When the level of phosphorylation of the mammalian target of rapamycin (mTOR) was measured, down-regulation of phosphorylated mTOR levels was observed only in rapamycin-treated cells. The LC3-positive granules in the U18666A-treated and cholesterol-depleted cells were different from those in rapamycin-treated cells in terms of number, size and distribution, suggesting that degradative process from autophagosomes to lysosomes was disturbed. DISCUSSION: The biochemical pathways leading to autophagy and the generation of AVs appear to be different in cells treated by the three methods. These differences may explain why the similar autophagic status determined by LC3 immunoreactivities does not correlate with Abeta generation and secretion.
Kouki Makioka; Tsuneo Yamazaki; Satoko Kakuda; Koichi Okamoto
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-02-11
Journal Detail:
Title:  Neurological research     Volume:  31     ISSN:  1743-1328     ISO Abbreviation:  Neurol. Res.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-11-06     Completed Date:  2010-02-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7905298     Medline TA:  Neurol Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  959-68     Citation Subset:  IM    
Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
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MeSH Terms
Alzheimer Disease / metabolism*,  physiopathology
Amyloid beta-Protein / biosynthesis*
Amyloid beta-Protein Precursor / genetics,  metabolism
Androstenes / pharmacology
Antibiotics, Antineoplastic / pharmacology
Autophagy / drug effects,  physiology*
CHO Cells
Cholesterol / deficiency
Down-Regulation / drug effects,  physiology
Enzyme Inhibitors / pharmacology
Intracellular Signaling Peptides and Proteins / metabolism
Microtubule-Associated Proteins / metabolism
Nerve Degeneration / metabolism*,  physiopathology
Neurons / metabolism,  pathology
Phagosomes / metabolism,  pathology
Phosphorylation / drug effects
Protein-Serine-Threonine Kinases / metabolism
Sirolimus / pharmacology
Vacuoles / metabolism,  pathology
Reg. No./Substance:
0/Amyloid beta-Protein; 0/Amyloid beta-Protein Precursor; 0/Androstenes; 0/Antibiotics, Antineoplastic; 0/Enzyme Inhibitors; 0/Intracellular Signaling Peptides and Proteins; 0/MAP1LC3 protein, mouse; 0/Microtubule-Associated Proteins; 3039-71-2/3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; 53123-88-9/Sirolimus; 57-88-5/Cholesterol; EC 2.7.1.-/mTOR protein; EC Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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