PMID- 19215663
OWN - NLM
STAT- MEDLINE
DCOM- 20100202
LR  - 20211203
IS  - 1743-1328 (Electronic)
IS  - 0161-6412 (Linking)
VI  - 31
IP  - 9
DP  - 2009 Nov
TI  - Variations in the effects on synthesis of amyloid beta protein in modulated 
      autophagic conditions.
PG  - 959-68
LID - 10.1179/174313209X395463 [doi]
AB  - 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.
FAU - Makioka, Kouki
AU  - Makioka K
AD  - Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, 
      Gunma, Japan.
FAU - Yamazaki, Tsuneo
AU  - Yamazaki T
FAU - Kakuda, Satoko
AU  - Kakuda S
FAU - Okamoto, Koichi
AU  - Okamoto K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090211
PL  - England
TA  - Neurol Res
JT  - Neurological research
JID - 7905298
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Androstenes)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Map1lc3b protein, mouse)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 3039-71-2 (3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Alzheimer Disease/*metabolism/physiopathology
MH  - Amyloid beta-Peptides/*biosynthesis
MH  - Amyloid beta-Protein Precursor/genetics/metabolism
MH  - Androstenes/pharmacology
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Autophagy/drug effects/*physiology
MH  - CHO Cells
MH  - Cholesterol/deficiency
MH  - Cricetinae
MH  - Cricetulus
MH  - Down-Regulation/drug effects/physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Microtubule-Associated Proteins/metabolism
MH  - Nerve Degeneration/*metabolism/physiopathology
MH  - Neurons/metabolism/pathology
MH  - Phagosomes/metabolism/pathology
MH  - Phosphorylation/drug effects
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Vacuoles/metabolism/pathology
EDAT- 2009/02/14 09:00
MHDA- 2010/02/03 06:00
CRDT- 2009/02/14 09:00
PHST- 2009/02/14 09:00 [entrez]
PHST- 2009/02/14 09:00 [pubmed]
PHST- 2010/02/03 06:00 [medline]
AID - ner1843 [pii]
AID - 10.1179/174313209X395463 [doi]
PST - ppublish
SO  - Neurol Res. 2009 Nov;31(9):959-68. doi: 10.1179/174313209X395463. Epub 2009 Feb 
      11.