The cellular prion protein (PrP) has been shown to act as a receptor for soluble oligomers of amyloid-beta (Aβ), an ~4 kDa amyloidogenic peptide that is found in neuritic plaques that are a pathological hallmark of Alzheimer’s disease (AD). Oligomeric forms of the Aβ peptide are thought to be synaptotoxic, and have been shown to produce PrP-dependent dendritic spine loss, suppression of long term potentiation (LTP), and behavioral changes in mouse models of AD. However, the specific molecular interactions between PrP and Aβ have not been fully characterized. In this work, we conducted a robust examination of the kinetic processes leading to Aβ fibril formation, and present evidence that PrP significantly inhibits Aβ polymerization. Using established mathematical models of polymerization kinetics, we show that inhibition is based on binding between PrP and the ends of Aβ filaments, an interaction that blocks elongation. To support these results, we conducted multiple binding assays to show that PrP binds to monomers of Aβ with low affinity, oligomers with intermediate affinity, and to fibrils with high affinity. These results extend upon previous studies, which have focused only on the interaction between oligomeric Aβ and PrP. To better understand the molecular interactions required for binding and inhibition of polymerization, we performed assays with a series of PrP deletion mutants, which revealed that low-affinity binding to Aβ monomer is dependent on the presence of the C-terminal domain of PrP. This domain is also required for Aβ polymerization inhibition. Based on our results, we propose a model in which the unstructured N-terminal domain of PrP binds to the ends of Aβ fibrils, while the C-terminal domain interrupts the docking of new monomers to fibril ends, in part through competing for similar binding sites. This study provides an important contribution to our understanding of the PrP-Aβ interaction that leads to synaptoxicity.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/23563 |
| Date | 10 July 2017 |
| Creators | Bove-Fenderson, Erin |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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