title: Cholesterol-depletion corrects APP and BACE1 misstrafficking in NPC1-deficient cells.
abstract: 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.
authors.affiliation: Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia.
authors.forename: Martina
authors.initials: M
authors.lastname: Malnar
authors.forename: Marko
authors.initials: M
authors.lastname: Kosicek
authors.forename: Ana
authors.initials: A
authors.lastname: Lisica
authors.forename: Melanija
authors.initials: M
authors.lastname: Posavec
authors.forename: Ana
authors.initials: A
authors.lastname: Krolo
authors.forename: Jasenka
authors.initials: J
authors.lastname: Njavro
authors.forename: Damir
authors.initials: D
authors.lastname: Omerbasic
authors.forename: Sabina
authors.initials: S
authors.lastname: Tahirovic
authors.forename: Silva
authors.initials: S
authors.lastname: Hecimovic
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000172:deficiency* / Q000378:metabolism*; D006224:Cricetinae; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D000736:Androstenes; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases