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dc.contributor.advisorWilliams, Joanna M.
dc.contributor.advisorTate, Warren P.
dc.contributor.authorElder, Megan Kate
dc.date.available2017-11-06T01:36:13Z
dc.date.copyright2017
dc.identifier.citationElder, M. K. (2017). Secreted amyloid precursor protein alpha regulates AMPA receptor synthesis and expression (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/7692en
dc.identifier.urihttp://hdl.handle.net/10523/7692
dc.description.abstractAmyloid precursor protein, the parent molecule of the neurotoxic amyloid beta protein associated with Alzheimer’s disease, can also liberate the secreted amyloid precursor protein alpha (sAPPα). This molecule facilitates long term potentiation (LTP) and spatial memory through mechanisms that are not yet fully elucidated, but is known to both modulate gene expression in a time-dependent manner, and induce local protein synthesis in isolated synapses. Protein synthesis is a requirement for the persistence of memory and LTP. Furthermore, regulation of the AMPA-subtype of glutamate receptors (AMPARs) is critical to LTP, and insertion of receptors containing the GluA1 and GluA2 subunits underlies synaptic potentiation. We aimed to investigate whether application of sAPPα (1 nM, 2 h) to cultured primary hippocampal neurons would modulate protein synthesis, including the AMPAR subunits GluA1 and GluA2. Using fluorescent non-canonical amino acid tagging with proximity ligation assays (FUNCAT-PLA) to label newly synthesized proteins, sAPPα was shown to enhance protein synthesis in cultured hippocampal neurons. Interestingly, a significant increase was observed in the synthesis of GluA1, but not the GluA2 AMPAR subunit. Furthermore, while the expression of new GluA1 was increased in the dendrites, de novo synthesis of GluA2 was decreased. Together, these findings suggest the synthesis of GluA1-containing AMPARs. FUNCAT-PLA labelling of new proteins on the neuronal surface revealed that fewer newly made proteins were expressed on the cell surface in response to sAPPα, and the surface expression of de novo-synthesized GluA1 was unaffected. However, increased expression of pre-existing GluA1 protein, in complex with GluA2 in heteromers, was observed on the neuronal surface indicating increased trafficking of existing AMPARs in response to sAPPα. Together, the findings suggest application of sAPPα to hippocampal neurons stimulates the synthesis of proteins including GluA1, but not GluA2. This specific increase suggests the rapid production of GluA1-containing receptors, that are not expressed on the neuronal surface by the completion of the 2 h experimental window. However, an increase in existing membrane-bound GluA1 protein is observed on the dendrites following incubation. The results provide a novel mechanism through which sAPPα enhances synaptic strength, priming the postsynaptic terminal for subsequent stimulation, and facilitating LTP.
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectAMPA receptor
dc.subjectsAPPα
dc.subjectAlzheimer's disease
dc.subjectprotein synthesis
dc.titleSecreted amyloid precursor protein alpha regulates AMPA receptor synthesis and expression
dc.typeThesis
dc.date.updated2017-11-05T22:08:49Z
dc.language.rfc3066en
thesis.degree.disciplineAnatomy
thesis.degree.nameDoctor of Philosophy
thesis.degree.grantorUniversity of Otago
thesis.degree.levelDoctoral
otago.interloanyes
otago.openaccessAbstract Only
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