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

Martina Malnar, Marko Kosicek, Stefan Mitterreiter, Damir Omerbasic, Stefan F. Lichtenthaler, Alison Goate, Silva Hecimovic

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)682-691
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1802
Issue number7-8
DOIs
StatePublished - Jul 2010
Externally publishedYes

Keywords

  • APP
  • Alzheimer's disease
  • Amyloid-β
  • Cholesterol
  • NPC1
  • β-secretase

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