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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1802

Article

Malnar, Martina¹  Kosicek, Marko¹  Mitterreiter, Stefan^2,3  Omerbasic, Damir¹  Lichtenthaler, Stefan F.^2,3  Goate, Alison⁴  Hecimovic, Silva¹ 

[1] Rudjer Boskovic Inst, Div Mol Med, Zagreb 10000, Croatia

[2] Univ Munich, DZNE, D-80336 Munich, Germany

[3] Univ Munich, Adolf Butenandt Inst, D-80336 Munich, Germany

[4] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

关键词: Alzheimer's disease;    Amyloid-beta;    APP;    Cholesterol;    beta-secretase;    NPC1;   

DOI  :  10.1016/j.bbadis.2010.05.006

来源: Elsevier

【 摘 要 】

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 beta-secretase pathway resulting in increased C99, sAPP beta and intracellular A beta 40 levels. This effect is dependent on increased cholesterol levels, since cholesterol depletion reversed cell surface APP expression and lowered A beta/C99 levels in NPC1(-/-) cells to the levels observed in wt cells. Finding that overexpression of C99, a direct gamma-secretase substrate, does not lead to increased intracellular A beta levels in NPC1(-/-) cells vs. CHOwt suggests that the effect on intracellular A beta upon cholesterol accumulation in NPC1(-/-) cells is not due to increased APP cleavage by gamma-secretase. Our results indicate that cholesterol may modulate APP processing indirectly by modulating APP expression at the cell surface and thus its cleavage by beta-secretase. (C) 2010 Elsevier B.V. All rights reserved.

【 授权许可】

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