Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disease. The candidate aetiological agent for this disease is the 4kDa amyloid beta (Ab) peptide which is derived from the proteolytic cleavage of the amyloid precursor protein (APP) by the b- and g-
secretase, respectively. As cellular prion proteins (PrPc) both regulate the cleavage of APP and mediate Ab induced neurotoxicity, a study was undertaken to establish whether the cellular receptor for PrPc, namely the 37kDa/67kDa laminin receptor (LRP/LR) also played a role in AD pathology. Anti LRP/LR specific antibody (IgG1-iS18) blocking LRP/LR resulted in a significant reduction of both Ab and sAPPb levels (the cleavage products of b-secretase), while APP, b- and g-secretase cell surface levels remained unaltered. LRP/LR was found to co-localise with APP, b- and g-secretase both on the cell surface and intracellularly. Furthermore, FRET demonstrated that an interaction existed between presenilin 1 (PS1) of the g-secretase and LRP/LR, while co-immunoprecipitation confirmed that LRP/LR interacted with both b-secretase and PS1. These results indicate that LRP/LR is implicated in the amyloidogenic processing of APP, through an indirect interaction with the b-secretase and a direct interaction with the g-secretase. These findings also suggest the possibility of utilising IgG1-iS18 as a possible therapeutic for the treatment of AD.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/14854 |
| Date | 02 July 2014 |
| Creators | Jovanovic, Katarina |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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