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Cholesterol and Alzheimer’s Disease-Related Pathology Open Access


Other title
Niemann-Pick type C1 protein
Mouse model
Endosomal-lysosomal system
Alzheimer’s disease
APP and Aβ metabolism
Tau phosphorylation and cleavage
Type of item
Degree grantor
University of Alberta
Author or creator
Maulik, Mahua
Supervisor and department
Kar, Satyabrata (Medicine and Psychiatry)
Examining committee member and department
Westaway, David (Medicine and Biochemistry)
Kar, Satyabrata (Medicine and Psychiatry)
Posse de Chaves, Elena (Pharmacology)
Baker, Glen (Psychiatry)
Quirion, Remi (Psychiatry)
Centre for Neuroscience

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Alzheimer’s disease (AD) is a complex neurodegenerative disorder believed to be triggered by the accumulation of β-amyloid (Aβ)-related peptides derived from the proteolytic processing of amyloid precursor protein (APP). Research over the last two decades 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-related peptides that are also the hallmarks of AD brains. To determine how alteration of the intracellular cholesterol level/distribution in the brain can influence the development of AD-related pathology, we have developed a new line of bigenic mice (ANPC) by crossing heterozygous Npc1-deficient mice with a well-established line of APP-transgenic mice (TgCRND8) overexpressing mutant human APP. The bigenic ANPC mice exhibited decreased life-span, accelerated cognitive and motor deficits and exacerbated glial as well as neuronal pathology including tau hyperphosphorylation/ cleavage, lysosomal dysfunction and neurodegeneration compared to littermates of other genotypes. Interestingly, reversal of cholesterol accumulation by 2-hydroxypropyl-β-cyclodextrin treatment was found to attenuate the observed behavioral and pathological abnormalities in ANPC mice, thus establishing the significance of cholesterol in the development of the pathology. Additionally, using ANPC mice and a complementary stable cell line, we have demonstrated that intracellular cholesterol accretion can influence APP processing and the autophagic-lysosomal degradation pathway, causing progressive accumulation of Aβ-related peptides which can render the cells vulnerable to oxidative injury. In summary, our results suggest that alterations in cholesterol homeostasis can influence a wide spectrum of behavioral and neuropathological abnormalities observed in AD-related pathology.
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. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. 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.
Citation for previous publication
Maulik, M., Ghoshal, B., Kim, J., Wang, Y., Yang, J., Westaway, D. and Kar, S. (2012) Mutant Human APP Exacerbates Pathology in a Mouse Model of NPC and its Reversal by a beta-cyclodextrin. Hum Mol Genet, 21, 4857-4875. Publisher: Oxford JournalsMaulik, M., Westaway, D., Jhamandas, J.H. and Kar, S. (2012) Role of Cholesterol in APP Metabolism and Its Significance in Alzheimer's Disease Pathogenesis. Mol Neurobiology. 2012 Sep16 (Epub ahead of print) Publisher: SpringerLink

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