Abstract
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.
Copyright 2010 Elsevier B.V. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / metabolism*
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Antigens, Surface / metabolism
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CHO Cells
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Carrier Proteins / genetics*
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Carrier Proteins / physiology
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Cells, Cultured
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Cholesterol / metabolism
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Cholesterol / pharmacology*
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Cricetinae
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Cricetulus
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins / genetics*
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Membrane Glycoproteins / physiology
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Niemann-Pick C1 Protein
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Niemann-Pick Disease, Type C / genetics
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Niemann-Pick Disease, Type C / metabolism
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Niemann-Pick Disease, Type C / pathology*
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Protein Processing, Post-Translational / drug effects
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transfection
Substances
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Amyloid beta-Protein Precursor
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Antigens, Surface
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Carrier Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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NPC1 protein, human
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Niemann-Pick C1 Protein
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Cholesterol
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Amyloid Precursor Protein Secretases