Cholesterol and Alzheimer’s Disease-Related Pathology

  • Author / Creator
    Maulik, Mahua
  • 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.

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  • Degree
    Doctor of Philosophy
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    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.
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  • Institution
    University of Alberta
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  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Quirion, Remi (Psychiatry)
    • Westaway, David (Medicine and Biochemistry)
    • Baker, Glen (Psychiatry)
    • Kar, Satyabrata (Medicine and Psychiatry)
    • Posse de Chaves, Elena (Pharmacology)