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Published on: January 25, 2018
Niemann-Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface and its increased
Martina Malnar1, Marko Kosicek, Stefan Mitterreiter
1Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia.
Biochimica Et Biophysica Acta
|May 25, 2010
Summary
High cholesterol levels in Niemann-Pick type C disease (NPC1(-/-) cells) decrease cell surface amyloid precursor protein (APP) and increase its processing via the beta-secretase pathway. Cholesterol depletion reverses these Alzheimer's disease-linked changes.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Cholesterol metabolism is increasingly linked to Alzheimer's disease (AD) pathogenesis.
- Niemann-Pick type C disease (NPC) is a lysosomal storage disorder characterized by cholesterol accumulation.
- Previous research suggests a connection between cholesterol and amyloid precursor protein (APP) processing in AD.
Purpose of the Study:
- To investigate the impact of cholesterol accumulation on APP processing in Niemann-Pick type C (NPC) disease models.
- To determine the role of cholesterol levels in regulating APP cell surface expression and proteolytic cleavage.
- To elucidate the specific pathways involved in APP metabolism affected by cholesterol dysregulation.
Main Methods:
- Utilized NPC1(-/-) cells and wild-type (wt) cells for comparative analysis.
- Assessed cell surface expression of APP using specific cellular assays.
- Quantified levels of APP metabolites, including C99, sAPPbeta, and intracellular Abeta40.
- Manipulated cellular cholesterol levels through depletion strategies.
Main Results:
- NPC1(-/-) cells exhibited reduced cell surface APP expression and elevated APP processing via the beta-secretase pathway.
- Increased intracellular levels of C99, sAPPbeta, and Abeta40 were observed in NPC1(-/-) cells.
- Cholesterol depletion in NPC1(-/-) cells normalized APP expression and Abeta/C99 levels to wt levels.
- Overexpression of C99 did not proportionally increase intracellular Abeta in NPC1(-/-) cells, suggesting gamma-secretase is not the primary affected pathway.
Conclusions:
- Cholesterol accumulation in NPC disease indirectly modulates APP processing.
- APP cell surface expression is sensitive to cellular cholesterol levels.
- Beta-secretase pathway activity is influenced by cholesterol, impacting Abeta generation.
- These findings highlight cholesterol as a potential therapeutic target for AD by modulating APP processing.
