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Effect of Cholesterol Accumulation on the Metabolism of Amyloid Precursor Protein (APP) in Cultured N2a Cells Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Chung, Jiyun
Supervisor and department
Kar, Satyabrata (Psychiatry)
Examining committee member and department
Winship, Ian (Psychiatry)
Kerr, Bradley (Pharmacology)
Sim, Valerie (Neurology)
Department of Psychiatry

Date accepted
Graduation date
Master of Science
Degree level
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder believed to be triggered by the accumulation of β-amyloid (Aβ) peptides derived from the proteolytic processing of amyloid precursor protein (APP). Accumulated evidence has shown that alterations in the levels and/or subcellular distribution of cholesterol can influence Aβ metabolism and development of AD pathology, but the underlying mechanisms remain unclear. A number of recent studies have shown that AD exhibits some striking parallels with Niemann-Pick Type C (NPC) disease – an autosomal recessive disorder caused primarily by loss-of-function mutations in the NPC1 gene. NPC disease, which is neuropathologically characterized by the intracellular accumulation of cholesterol, exhibits tau-positive neurofibrillary tangles and increased levels of Aβ peptides that are also the hallmarks of AD brains. To determine how alterations of intracellular cholesterol levels/distribution can influence APP processing, we evaluated the effects of U18666A, a class II amphiphile which triggers intracellular redistribution of cholesterol, on cultured N2awt, APPwt and APPsw cells in the presence and absence of different concentrations of fetal bovine serum (FBS). Our results revealed that U18666A treatment, but not increasing concentrations of FBS, triggered accumulation of cholesterol in cultured N2awt, APPwt and APPsw cells. U18666A treatment, but not FBS concentrations, differentially increased levels of APP and its cleaved products α-CTF and β-CTF in N2awt, APPwt and APPsw cells. The levels of APP secreatses and their activities remained unaltered following U18666A treatment in all three cell lines, but the cellular levels of Aβ1-40 and Aβ1-42 were markedly increased in APPwt or APPsw cells. Collectively, these results suggest that cholesterol accumulation can significantly influence APP levels and its metabolism, especially in cells stably overexpressing either wild-type or mutant human APP.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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