Cholesterol-depletion corrects APP and BACE1 misstrafficking in NPC1-deficient cells

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1822

Article

Malnar, Martina¹  Kosicek, Marko¹  Lisica, Ana¹  Posavec, Melanija¹  Krolo, Ana¹  Njavro, Jasenka¹  Omerbasic, Damir¹  Tahirovic, Sabina²  Hecimovic, Silva¹ 

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

[2] German Ctr Neurodegenerat Dis DZNE, D-80336 Munich, Germany

关键词: Alzheimer's disease;    APP;    BACE1;    Cholesterol;    Endocytosis;    NPC1;   

DOI  :  10.1016/j.bbadis.2012.04.002

来源: Elsevier

【 摘 要 】

Cholesterol accumulation in Niemann-Pick type C disease (NPC) causes increased levels of the amyloid-precursor-protein C-terminal fragments (APP-CTFs) and intracellular amyloid-beta peptide (A beta), the two central molecules in Alzheimer's disease (AD) pathogenesis. We previously reported that cholesterol accumulation in NPC-cells leads to cholesterol-dependent increased APP processing by beta-secretase (BACE1) and decreased APP expression at the cell surface (Malnar et al. Biochim Biophys Acta. 1802 (2010) 682-691.). We hypothesized that increased formation of APP-CTFs and A beta in NPC disease is due to cholesterol-mediated altered endocytic trafficking of APP and/or BACE1. Here, we show that APP endocytosis is prerequisite for enhanced A beta levels in NPC-cells. Moreover, we observed that NPC cells show cholesterol dependent sequestration and colocalization of APP and BACE1 within enlarged early/recycling endosomes which can lead to increased beta-secretase processing of APP. We demonstrated that increased endocytic localization of APP in NPC-cells is likely due to both its increased internalization and its decreased recycling to the cell surface. Our findings suggest that increased cholesterol levels, such as in NPC disease and sporadic AD, may be the upstream effector that drives amyloidogenic APP processing characteristic for Alzheimer's disease by altering endocytic trafficking of APP and BACE1. (C) 2012 Elsevier B.V. All rights reserved.

【 授权许可】

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