Secreted amyloid precursor protein alpha as a therapeutic for insulin signaling dysfunction in the nervous system
| dc.contributor.author | Aulston, Brent | |
| dc.contributor.examiningcommittee | Albensi, Benedict (Pharmacology and Therapeutics) Hatch, Grant (Pharmacology and Therapeutics) Czubryt, Michael (Physiology and Pathophysiology) Prado, Marco (Western University) | en_US |
| dc.contributor.supervisor | Glazner, Gordon (Pharmacology and Therapeutics) | en_US |
| dc.date.accessioned | 2018-09-10T15:08:45Z | |
| dc.date.available | 2018-09-10T15:08:45Z | |
| dc.date.issued | 2018-08-20 | en_US |
| dc.date.submitted | 2018-08-20T16:13:27Z | en |
| dc.degree.discipline | Pharmacology and Therapeutics | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Background: The amyloid precursor protein (APP) cleavage product secreted amyloid precursor protein alpha (sAPPα) is a neurotrophic factor demonstrated to be protective to neurons. Despite evidence that sAPPα activates the insulin signaling ,the effects of sAPPα on diabetes-induced pathology are unknown. Hypothesis: We hypothesized that sAPPα could inhibit neuronal dysfunction in an animal model of diabetes. This hypothesis was tested in 3 aims. AIM 1: To determine if sAPPα could inhibit the development of Alzheimer’s-like pathology in diabetic brain tissue. AIM 2: To examine if sAPPα could slow the development of diabetes-induced peripheral neuropathy. AIM 3: In our final aim, we examined the effects of sAPPα overexpressing neural stem cells (sAPPα-NSCs) engrafted into the hippocampi on Morris water maze (MWM) performance of healthy mice. Results: Analysis of brain tissue from diabetic sAPPα mice revealed that sAPPα blocked the development of Alzheimer’s-like pathology in the form of aberrant tau phosphorylation. Additionally, sAPPα decreased diabetes-induced activation of the unfolded protein response (UPR), a sign that diabetic sAPPα mice maintained better overall brain health compared to diabetic controls. We found that sAPPα slowed the development of diabetes-induced thermal hypoalgesia, an indicator of sensory neuropathy, in our model. Cell culture experiments demonstrated that the neurotrophic effects of sAPPα in the PNS are associated with up-regulation of the neuroprotective transcription factor NFκB and increased expression of the mitochondrial antioxidant MnSOD. In the final set of experiments, we found that hippocampal injections of sAPPα-NSCs altered Morris water maze (MWM) performance of healthy SAMR1 mice. Although future studies are required to determine the effects of sAPPα-NSCs on cognition, these preliminary results nevertheless warrant future studies investigating the therapeutic potential of sAPPα-NSCs. Conclusion: In total, the results presented in this thesis demonstrate that sAPPα can inhibit pathology in the diabetic nervous system. Therefore, the data generated from these studies has provided a foundation for the development of sAPPα based therapeutics, potentially in the form of sAPPα-NSCs, as a treatment option for diabetes and AD. | en_US |
| dc.description.note | October 2018 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/33269 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Diabetes | en_US |
| dc.subject | Alzheimer's disease | en_US |
| dc.subject | Neuropathy | en_US |
| dc.subject | Secreted APP alpha | en_US |
| dc.title | Secreted amyloid precursor protein alpha as a therapeutic for insulin signaling dysfunction in the nervous system | en_US |
| dc.type | doctoral thesis | en_US |