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


Other title
Amyloid beta peptide
Protein prenylation
Type of item
Degree grantor
University of Alberta
Author or creator
Mohamed, Amany
Supervisor and department
Dr. Posse de Chaves, Elena (Pharmacology)
Examining committee member and department
Dr. Karten, Barbara (Biochemistry and Molecular Biology-Dalhousie University)
Dr. Posse de Chaves, Elena (Pharmacology)
Dr. Kar, Satya (Psychiatry)
Dr. Holt, Andy (Pharmacology)
Dr. Berthiaume, Luc (Cell Biology)
Dr. Sipione, Simonetta (Pharmacology)
Department of Pharmacology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
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.
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
Mohamed, A., and E. Posse de Chaves. (2011). Abeta internalization by neurons and glia. Int J Alzheimers Dis. 2011:127984
, A., L. Cortez, and E.P. de Chaves. 2011. Aggregation State and Neurotoxic Properties of Alzheimer beta-Amyloid Peptide. Curr Protein Pept Sci. 12:235-257
, A., Saavedra, L., Di Pardo, A., Sipione, S., and Posse de Chaves, E. 2012. beta-amyloid inhibits protein prenylation and induces cholesterol sequestration by impairing SREBP-2 cleavage. J. Neurosci. 32(19): 6490-500.

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