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

Malnar, Martina; Košiček, Marko; Lisica, Ana; Posavec, Melanija; Krolo, Ana; Njavro, Jasenka; Omerbašić, Damir; Tahirović, Sabina; Hećimović, Silva (2012) Cholesterol-depletion corrects APP and BACE1 misstrafficking in NPC1-deficient cells. Biochimica et biophysica acta-molecular basis of disease, 1822 (8). pp. 1270-1283. ISSN 0925-4439

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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-β peptide (Aβ), 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 β-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 Aβ 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 Aβ 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 β-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.

Item Type: Article
Uncontrolled Keywords: Alzheimer’s disease; APP; BACE1; cholesterol; endocytosis; NPC1
Subjects: NATURAL SCIENCES > Biology
NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Neuroscience
Divisions: Division of Molecular Medicine
Project titleProject leaderProject codeProject type
The mechanism of cholesterol action in the pathogenesis of Alzheimer's disease (Mehanizam djelovanja kolesterola u nastanku Alzheimerove bolesti)-Silva Katušić Hećimović098-0982522-2525MZOS
Depositing User: Martina Malnar
Date Deposited: 03 Dec 2015 10:42
DOI: 10.1016/j.bbadis.2012.04.002

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