A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 2014. / Alzheimer’s Disease (AD) is characterized by neurofibrillary tangles, senile plaques and
neuronal loss. Although the mechanisms underlying Amyloid beta 42 (Aβ42) neurotoxicity
have not been firmly established, it is proposed that the neuronal loss is elicited through
associations with cell surface receptors. The cellular prion protein (PrPc) has been identified
as an Aβ42 receptor and as a regulator of the amyloidogenic cleavage pathway. As Aβ42
shares common binding partners with the 37kDa/67kDa laminin receptor (LRP/LR),
including PrPc, we investigated whether these proteins interact and assessed the pathological
significance of this association. LRP/LR was found to co-localize with Aβ on the cell surface.
The occurrence of FRET suggested that an interaction between LRP/LR and Aβ indeed exists
at the cell surface. Furthermore, pull down assays and Aβ-specific ELISAs demonstrated that
LRP/LR forms a physical association with endogenously shed Aβ, thereby verifying the
physiological relevance of this association. Antibody blockade by IgG1-iS18 and shRNAmediated
downregulation of LRP/LR significantly enhanced cell viability and proliferation
and decreased apoptosis in cells co-treated with Aβ42 when compared to cells incubated with
Aβ42 alone. In addition, antibody blockade and shRNA-mediated downregulation of LRP/LR
significantly impeded Aβ42 internalization. These results suggest that LRP/LR acts as an
internalization receptor for Aβ42 and may thereby contribute to the cytotoxicity of the
neuropeptide by facilitating intracellular Aβ42 accumulation and aggregation - which has
consequences for cell proliferation and may promote apoptosis. These findings recommend
anti-LRP/LR specific antibodies and shRNAs as potential therapeutic tools for Alzheimer’s
Disease treatment.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/15605 |
| Date | 23 September 2014 |
| Creators | Dias, Bianca Da Costa |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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