Niemann Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface its increased processing through the β-secretase pathway

Martina Malnar (1) , Marko Kosicek (1) , Stefan Mitterreiter (2) , Damir Omerbasic (1) , Stefan F. Lichtenthaler (2) , Alison Goate (3) , Silva Hecimovic (1)

1 Division of Molecular Medicine
2 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
3 Department of Psychiatry

The link between cholesterol and Alzheimer's disease has recently been revealed in Niemann Pick type C disease. We found that 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 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 cells CHOwt suggests that the effect on intracellular Aβ upon cholesterol accumulation in 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.

Mots clés: AD; APP; ApoE; AICD; Aβ; CTFs; DAPT; FA; flAPP; LPDS; NPC; SEAP; sAPP; Alzheimer's disease; amyloid-β; cholesterol; β-secretase; NPC1

Martina Malnar, Marko Kosicek, Stefan Mitterreiter, Damir Omerbasic, Stefan F. Lichtenthaler, et al.. Niemann Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface its increased processing through the β-secretase pathway. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2010, 1802 (7-8), pp.682. ⟨10.1016/j.bbadis.2010.05.006⟩. ⟨hal-00600129⟩