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Title: The cellular prion protein as a receptor for amyloid-beta oligomers
Author: Rushworth, Joanne Valerie Humphrey
ISNI:       0000 0004 2746 6521
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Alzheimer's disease (AD), a progressive, neurodegenerative brain disorder, is an impending socio-economic crisis due to the aging global population. Soluble oligomers of the amyloid-β (Aβ) peptide cause neurotoxicity, synaptic dysfunction and memory impairments which underlie AD, but their mechanisms of action are poorly understood. Recently, the cellular prion protein (Prpc) was identified as a high affinity receptor which mediates the neuronal binding and memory impairments of AI3 oligomers. In this study, the cellular biology of the interaction between AI3 oligomers and Prpc was investigated. We report that fibrillar Aβ oligomers recognised by the QC antibody, which have been shown to correlate with the onset and severity of AD, bind preferentially to neuronal cells expressing Prpc. The green tea polyphenol (-)-epigallocatechin gallate (EGCG) and the red wine extract resveratrol both re-modelled the fibrillar conformation of AI3 oligomers. The resulting non-fibrillar oligomers displayed significantly reduced binding to Prpc-expressing cells and were no longer cytotoxic. Fluorescence microscopy and co-localisation with sub-cellular markers revealed that the AI3 oligomers co-internalised with Prpc, accumulated in endosomes and subsequently trafficked to Iysosomes. We report that the cell surface binding, internalisation and downstream toxicity of Aβ oligomers is dependent on the transmembrane low density lipoprotein receptor- related protein-1 (LRP1). Western blotting revealed that the binding of AI3 oligomers to cell surface Prpc impaired its ability to inhibit the activity of the l3-secretase BACE1 which cleaves the amyloid precursor protein to produce AI3. Using an siRNA approach, AI3 oligomers were found to activate the signalling molecule STEP61 in a Prpc-dependent manner. AI3 oligomers also stimulated caspase-3 activation via Prpc. These data indicate that soluble, fibrillar Aβ oligomers bind to Prpc in a conformation-dependent manner and require the transmembrane LRP1 for their cytotoxicity, thus revealing potential targets for therapeutic intervention in AD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available