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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

Malnar, Martina; Košiček, Marko; Mitterreiter, Stefan; Omerbašić, Damir; Lichtenthaler, Stefan F.; Goate, Alison; Hećimović, Silva (2010) 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 diseas, 1802 (7/8). pp. 682-691. ISSN 0925-4439

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Abstract

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 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 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 Aβ levels in NPC1-/- cells vs. CHOwt suggests that the effect on intracellular Aβ 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 β-secretase.

Item Type: Article
Uncontrolled Keywords: Alzheimer’s disease; amyloid-β; APP; cholesterol; β-secretase; NPC1
Subjects: NATURAL SCIENCES > Biology
NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Neuroscience
Divisions: Division of Molecular Medicine
Projects:
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 10:34
Last Modified: 03 Dec 2015 13:01
URI: http://fulir.irb.hr/id/eprint/2387
DOI: 10.1016/j.bbadis.2010.05.006

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