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Type: Thesis
Title: The role of the amyloid precursor protein following traumatic brain injury.
Author: Corrigan, Frances
Issue Date: 2011
School/Discipline: School of Medical Sciences
Abstract: The amyloid precursor protein (APP) is known to increase following traumatic brain injury (TBI). It has been hypothesised that this increase in APP may be deleterious to outcome due to the production of neurotoxic Aβ. Conversely, this upregulation may be beneficial as cleavage of APP via the alternative non-amyloidogenic pathway produces the soluble alpha form of APP (sAPPα), which is known to have many neuroprotective and neurotrophic functions. Indeed a previous study showed that treatment with sAPPα following a diffuse injury in rats reduced apoptotic cell death and axonal injury which corresponded with an improvement in motor outcome. However, it is not yet known whether endogenous APP plays a similar beneficial role following TBI, or which specific region within sAPPα conferred this protective activity. In order to investigate this the effect of post-traumatic administration of various regions within sAPPα was examined following severe-impact acceleration TBI in Sprague Dawley rats. Furthermore the outcome of male C57BL6j x 129sv APP-/- mice was compared to that of APP+/+ mice following two types of traumatic brain injury; a diffuse lesion caused by a weight drop model and a focal lesion induced by a controlled cortical impact (CCI) injury. Knockout of APP was found to worsen outcome following both a mild diffuse and moderate focal injury, with an exacerbation of motor and cognitive deficits associated with an increase in neuronal injury and an impaired reparative response. These deficits could be rescued with treatment with sAPPα, suggesting that it was lack of this APP metabolite which caused the increase in vulnerability of APP-/- mice. Furthermore initial investigations in Sprague Dawley rats found that only the domains of sAPPα that contained heparin binding sites were able to improve functional outcome and decrease axonal injury following diffuse TBI. This suggested that the neuroprotective activity of sAPPα related to its ability to bind to heparin sulphate proteoglycans. Indeed a preliminary investigation found that the peptide APP96-110, which encompassess one of the heparin binding sites within sAPPα, was sufficient to reduce functional deficits and neuronal injury in APP-/- mice. These results demonstrate that the upregulation of APP seen following TBI is a protective response, with the benefits of sAPPα outweighing any negative effects of other APP metabolites like Aβ. The neuroprotective properties of sAPPα, may relate to its heparin binding sites, with one of these regions, APP96-110, warranting further investigation as a putative neuroprotective agent following TBI.
Advisor: Van Den Heuvel, Corinna
Vink, Robert
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2011
Keywords: amyloid precursor protein; traumatic brain injury; sAPPα
Appears in Collections:Research Theses

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