The link between cholesterol and Alzheimer's disease has recently been revealed in Niemann-Pick type C disease. We found that NPC1β/β cells show decreased expression of APP at the cell surface and increased processing of APP through the β-secretase pathway resulting in increased C99, sAPPβ and intracellular Aβ40 levels. This effect is dependent on increased cholesterol levels, since cholesterol depletion reversed cell surface APP expression and lowered Aβ/C99 levels in NPC1β/β cells to the levels observed in wt cells. Finding that overexpression of C99, a direct β-secretase substrate, does not lead to increased intracellular Aβ levels in NPC1β/β cells vs. CHOwt suggests that the effect on intracellular Aβ upon cholesterol accumulation in NPC1β/β cells is not due to increased APP cleavage by β-secretase. Our results indicate that cholesterol may modulate APP processing indirectly by modulating APP expression at the cell surface and thus its cleavage by β-secretase.
|Number of pages||10|
|Journal||Biochimica et Biophysica Acta - Molecular Basis of Disease|
|State||Published - Jul 2010|
- Alzheimer's disease