A!dissertation submitted to the Faculty of Science, University of the
Witwatersrand, Johannesburg, in the fulfillment of the requirements for the
degree of Master of Science. 2013. / Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease affecting
in excess of 26.6 million individuals globally. The neuropathological features of AD
include extracellular deposition of amyloid beta (Aβ) plaques and intracellular
neurofibrillary tangle formation. The cellular prion protein (PrPC) regulates the
amyloidogenic cleavage pathway involved in Aβ shedding and interacts with the Aβ
peptide. Given these interactions, the aim of this study was to investigate the
influence of the 37kDa/67kDa laminin receptor (LRP/LR)- the cellular receptor for
prion proteins- on Aβ shedding. Transfection of HEK293 cells with short hairpin
RNAs (shRNAs) directed against LRP mRNA significantly decreased LRP levels in
addition to Aβ shedding. Flow cytometric analysis revealed unchanged cell surface
levels of the amyloid precursor protein (APP), β-secretase and γ-secretase after
transfection of cells with shRNAs, suggesting a role of LRP/LR in Aβ shedding via a
mechanism independent of gene-expression modulation of these key proteins. LRPshRNA
treatment significantly reduced sAPPβ expression, implicating LRP/LR in
APP processing specifically via augmenting the activity of β-secretase. Colocalisation
of LRP/LR with APP, β- and γ-secretase, respectively, alludes to a
possible interaction between said proteins. Therefore, LRP-shRNAs are suggested as
alternative therapeutic tools for AD treatment.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/12908 |
| Date | 26 July 2013 |
| Creators | Gonsalves, Danielle |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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