Niemann–Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface and its increased processing through the β-secretase pathway |
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Authors: | Martina Malnar Marko Kosicek Stefan Mitterreiter Damir Omerbasic Stefan F Lichtenthaler Alison Goate Silva Hecimovic |
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Institution: | 1. Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia;2. Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) & Adolf Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University, Schillerstr. 44, 80336 Munich, Germany;3. Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA |
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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 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 NPC1?/? cells to the levels observed in wt cells. Finding that overexpression of C99, a direct γ-secretase substrate, does not lead to increased intracellular Aβ levels in NPC1?/? cells vs. CHOwt suggests that the effect on intracellular Aβ upon cholesterol accumulation in NPC1?/? cells is not due to increased APP cleavage by γ-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. |
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