Document Detail


Niemann-Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface and its increased processing through the beta-secretase pathway.
MedLine Citation:
PMID:  20493254     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The link between cholesterol and Alzheimer's disease has recently been revealed in Niemann-Pick type C disease. We found that NPC1(-/-) cells show decreased expression of APP at the cell surface and increased processing of APP through the beta-secretase pathway resulting in increased C99, sAPPbeta and intracellular Abeta40 levels. This effect is dependent on increased cholesterol levels, since cholesterol depletion reversed cell surface APP expression and lowered Abeta/C99 levels in NPC1(-)(/)(-) cells to the levels observed in wt cells. Finding that overexpression of C99, a direct gamma-secretase substrate, does not lead to increased intracellular Abeta levels in NPC1(-)(/)(-) cells vs. CHOwt suggests that the effect on intracellular Abeta upon cholesterol accumulation in NPC1(-)(/)(-) cells is not due to increased APP cleavage by gamma-secretase. Our results indicate that cholesterol may modulate APP processing indirectly by modulating APP expression at the cell surface and thus its cleavage by beta-secretase.
Authors:
Martina Malnar; Marko Kosicek; Stefan Mitterreiter; Damir Omerbasic; Stefan F Lichtenthaler; Alison Goate; Silva Hecimovic
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-05-20
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1802     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:    2010 Jul-Aug
Date Detail:
Created Date:  2010-06-28     Completed Date:  2010-08-10     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  682-91     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier B.V. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Amyloid Precursor Protein Secretases / metabolism*
Amyloid beta-Protein Precursor / metabolism*
Animals
Antigens, Surface / metabolism
CHO Cells
Carrier Proteins / genetics*,  physiology
Cell Membrane / drug effects,  metabolism
Cells, Cultured
Cholesterol / metabolism,  pharmacology*
Cricetinae
Cricetulus
Membrane Glycoproteins / genetics*,  physiology
Niemann-Pick Disease, Type C / genetics,  metabolism,  pathology*
Protein Processing, Post-Translational / drug effects
Signal Transduction / drug effects,  physiology
Transfection
Grant Support
ID/Acronym/Agency:
R03 TW007335/TW/FIC NIH HHS; R03 TW007335-01/TW/FIC NIH HHS; R03 TW007335-02/TW/FIC NIH HHS; R03 TW007335-03/TW/FIC NIH HHS; R03TW007335-01/TW/FIC NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid beta-Protein Precursor; 0/Antigens, Surface; 0/Carrier Proteins; 0/Membrane Glycoproteins; 0/NPC1 protein, human; 97C5T2UQ7J/Cholesterol; EC 3.4.-/Amyloid Precursor Protein Secretases
Comments/Corrections

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