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dc.contributor.advisor Lo, Donald C en_US
dc.contributor.advisor Chikaraishi, Dona en_US
dc.contributor.author Christianson, Melissa Gottron en_US
dc.date.accessioned 2012-05-25T20:08:55Z
dc.date.issued 2012 en_US
dc.identifier.uri http://hdl.handle.net/10161/5427
dc.description Dissertation en_US
dc.description.abstract <p>Hypoxia is a profound stressor of the central nervous system implicated in numerous neurodegenerative diseases. While it is increasingly evident that the early effects of hypoxia cause impairment at the level of the axon, the precise mechanisms through which hypoxia compromises axonal structure and function remain unclear. However, links between hypoxia-induced axonopathic disease and the amyloid cascade, as well as the upregulation of amyloid precursor protein (APP) and amyloid beta (A&beta;) by hypoxic stress, give rise to the hypothesis that proteolytic cleavage of APP into A&beta; may be specifically responsible for axonopathy under conditions of hypoxia. </p><p>The goal of this dissertation was thus to understand dependence of hypoxia-induced axonal morphological and functional impairment on APP cleavage and the production of A&beta;. I have developed a model of hypoxia-induced axonopathy in retinal explants. Using this model, I have experimentally addressed the core hypothesis that APP cleavage, and in particular the formation of A&beta;, is necessary and sufficient to mediate morphological and functional axonopathy caused by hypoxia. I have found that there is a dissociation between the mechanisms responsible for hypoxia-induced morphological and functional impairment of the axon in the explanted retina, with the former being dependent on APP-to-A&beta; processing and the latter likely being dependent on cleavage of a non-APP substrate by the enzyme BACE1. These findings shed light on mechanisms of hypoxia-induced axonopathy.</p> en_US
dc.subject Neurosciences en_US
dc.subject Alzheimer's disease en_US
dc.subject Amyloid Beta en_US
dc.subject Amyloid Precursor Protein en_US
dc.subject Axon en_US
dc.subject Hypoxia en_US
dc.subject Neurodegeneration en_US
dc.title Amyloid Precursor Protein-Dependent and -Independent Mechanisms in Hypoxia-Induced Axonopathy en_US
dc.type Dissertation en_US
dc.department Neurobiology en_US
duke.embargo.months 24 en_US
duke.embargo.release 2014-05-15

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