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

  • Author / Creator
    Chung, Jiyun
  • 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.

  • Subjects / Keywords
  • Graduation date
    2015-11
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R32H3S
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Master's
  • Department
    • Department of Psychiatry
  • Supervisor / co-supervisor and their department(s)
    • Kar, Satyabrata (Psychiatry)
  • Examining committee members and their departments
    • Winship, Ian (Psychiatry)
    • Kerr, Bradley (Pharmacology)
    • Sim, Valerie (Neurology)