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dc.contributor.authorFluharty, Brian Richarden_US
dc.date.accessioned2015-08-18T17:23:06Z
dc.date.available2015-08-18T17:23:06Z
dc.date.issued2013
dc.date.submitted2013
dc.identifier.other(ALMA)contemp
dc.identifier.urihttps://hdl.handle.net/2144/12955
dc.descriptionThesis (Ph.D.)--Boston Universityen_US
dc.description.abstractAlzheimer's disease (AD) is characterized by progressive dementia and accumulation of a cleavage product of the amyloid precursor protein, amyloid-β (Aβ) peptide, in the brain. Several lines of evidence suggest that soluble, oligomeric intermediates of Aβ are primarily responsible for synaptic dysfunction and the cognitive deficit observed in AD. The cellular prion protein (PrP^c), a cell surface glycoprotein involved in transmissible spongiform encephalopathies, was previously identified as a high affinity receptor for Aβ oligomers. It has been suggested that binding of Aβ oligomers to PrP^c transduces the synaptotoxic events seen in AD. The two reported binding sites of Aβ oligomers are located on the unstructured N-terminal tail of PrP^c. We show here that the soluble physiological cleavage fragment of PrP^c, N1, was necessary and sufficient for binding Aβ oligomers. This binding interaction was influenced by positively charged residues in the two binding sites and is dependent on the length ofthe sequence between them. Importantly, the addition of synthetic N1 peptide suppressed Aβ oligomer toxicity in cultured murine hippocampal neurons and in a mouse model of Aβ-induced memory dysfunction. Collectively, these data suggest that N1, or small peptides derived from it, could be potent inhibitors of Aβ oligomer toxicity by targeting Aβ oligomers and represent an entirely new class of therapeutic agents for AD. To directly target PrP^c as a toxicity receptor, in silica screening and molecular dynamics were used to generate small molecule ligands. We screened these ligands using biochemical and biophysical assays to identify high affinity ligands for PrP^c that block the binding of Aβ oligomers. We found one compound, called DS26 that bound to PrP^c with sub-micromolar affinity. Further, DS26 inhibited Aβ-dependent suppression of long-term potentiation in mouse hippocampal slices. Interestingly, we show that DS26 operated by an unexpected allosteric mechanism in which ligand binding to a site in the structured C-terminal half of PrP^c induced an intramolecular interaction with the N-terminal tail, thereby preventing Aβ binding. Together, these data demonstrate that pharmacologically targeting PrP^c can suppress Aβ toxicity. Additionally, this study clarifies previous conflicting studies regarding the role of PrP^c in AD.en_US
dc.language.isoen_US
dc.publisherBoston Universityen_US
dc.titleIdentification of novel cellular prion protein-based compounds to block the toxicity of amyloid-beta oligomersen_US
dc.typeThesis/Dissertationen_US
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineBiochemistryen_US
etd.degree.grantorBoston Universityen_US


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