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Amyloid beta peptide, Cholesterol and Isoprenoids in Alzheimer’s disease

  • Author / Creator
    Mohamed, Amany
  • Alzheimer’s disease (AD) is the most common form of dementia in the elderly. The major pathological features of AD are extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss. Amyloid beta (Aβ) peptide, the main component of the amyloid plaques, has been proposed to be the initiator of most of the pathological changes that occur in AD (Amyloid Hypothesis). Mounting genetic, epidemiological and biochemical evidence indicate the involvement of cholesterol in AD pathology. Cholesterol accumulation has been confirmed in AD brain and has demonstrated to play a role in AD pathology, however, the origin of this cholesterol accumulation has not been identified yet. In this thesis we examined the regulation of cholesterol homeostasis by oligomers of Aβ42 (oAβ42) in primary neurons. We demonstrated for the first time that oAβ42 causes intracellular cholesterol sequestration at the late endosome/lysosome, the Golgi and the plasma membrane. Subsequently, we investigated the mechanism underlying oAβ42-induced cholesterol sequestration. We discovered that oAβ42 inhibits the maturation of the transcription factor; sterol regulatory element binding protein-2 (SREBP-2), which is crucial for the synthesis of isoprenoids. As a result we demonstrated for the first time that protein prenylation of small GTPases is reduced in oAβ42-treated neurons as well as in cortices of TgCRND8, an AD transgenic mouse model. Hence, exogenous supply of geranylgeranyl pyrophosphate (GGPP) was able to restore normal protein prenylation, prevent cholesterol sequestration and reduce neurotoxicity in oAβ42-treated neurons. Our work revealed that oAβ42-induced inhibition of protein prenylation is a novel mechanism of oAβ42-induced cholesterol sequestration and neurotoxicity. Furthermore, we illustrated that oAβ42-induced reduction of phosphorylated Akt leads to reduced SREBP-2 transport from the endoplasmic reticulum to the Golgi leading to reduced SREBP-2 processing. Our work provided an evidence that cholesterol sequestration and impaired cholesterol trafficking in AD is induced by oAβ42. Moreover, we identified SREBP-2 and protein prenylation as new targets of oAβ42, which opens a new area of research investigating the role of oAβ42-induced inhibition of SREBP-2 processing and consequent inhibition of protein prenylation in the development of many pathological changes observed in AD.

  • Subjects / Keywords
  • Graduation date
    2014-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3K06X862
  • 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
    Doctoral
  • Department
    • Department of Pharmacology
  • Supervisor / co-supervisor and their department(s)
    • Dr. Posse de Chaves, Elena (Pharmacology)
  • Examining committee members and their departments
    • Dr. Kar, Satya (Psychiatry)
    • Dr. Karten, Barbara (Biochemistry and Molecular Biology-Dalhousie University)
    • Dr. Posse de Chaves, Elena (Pharmacology)
    • Dr. Holt, Andy (Pharmacology)
    • Dr. Sipione, Simonetta (Pharmacology)
    • Dr. Berthiaume, Luc (Cell Biology)