Reelin, stress, and inflammation: Implications for treatment of major depression and diagnosis of Alzheimer’s disease
| dc.contributor.author | Reive, Brady S. | |
| dc.contributor.supervisor | Caruncho, Hector | |
| dc.contributor.supervisor | Kalynchuk, Lisa | |
| dc.date.accessioned | 2025-01-21T17:53:35Z | |
| dc.date.available | 2025-01-21T17:53:35Z | |
| dc.date.issued | 2025 | |
| dc.degree.department | Division of Medical Sciences | |
| dc.degree.level | Doctor of Philosophy PhD | |
| dc.description.abstract | Reelin has been recognized for playing a role in various neuropsychiatric disorders including major depression and Alzheimer’s disease (AD). It was demonstrated that Reelin signaling is implicated in various molecular pathways that are affected in these disorders, including but not limited to trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) required for long-term potentiation and synaptic plasticity, regulation of amyloid beta and the phosphorylation of tau. Both major depression and AD are marked by reduced Reelin expression and alterations to Reelin cleavage. More recently, it has been shown that Reelin can be administered to animals exposed to chronic stress to relieve depression-like behaviour and spatial memory deficits associated with chronic stress exposure. While it has long been recognized that inflammatory processes contribute to both major depression and AD pathogenesis, it was only recently shown that Reelin expression is altered with inflammatory challenges and in several inflammatory conditions, including COVID-19. The observation that Reelin possesses antidepressant-like properties and inflammatory functions suggests Reelin dysregulation could contribute to inflammatory changes observed in depression and Alzheimer’s. Although altered Reelin expression has been shown in disorders of inflammation, depression and AD, it is currently unknown whether administration of recombinant Reelin modifies inflammatory processes, or in other words, whether there exists a bidirectional relationship between Reelin expression and inflammatory processes. With this research, evidence is provided showing exogenous Reelin administration can modulate inflammatory processes in chronic stress and non-stressed conditions. Additionally, it has been shown that a blood-based biomarker for depression is modulated by Reelin signaling. Early findings related to this biomarker, membrane protein clustering of the serotonin transporter protein on peripherally circulating lymphocytes, show this biomarker can reliably differentiate depressed from non-depressed controls. Additionally, within depressed populations this biomarker can identify those that will respond to treatment and those that are likely to be resistant to antidepressant treatment effects. However, large-scale validation studies for this biomarker have yet to be conducted, in part due to the massive manual labour requirements for analyzing membrane protein clustering. This led to the development of an automated method for analyzing membrane protein clustering, which is outlined in Chapter 5 of this thesis. Finally, while it is known that Reelin can modify membrane protein clustering and more neuropsychiatric conditions are marked by dysregulation of Reelin signaling than just major depression, there has yet to be an assessment of membrane protein clustering in many of these additional conditions (ex. epilepsy, multiple sclerosis, AD, etc.). This led to the evaluation of membrane protein clustering in a small sample of individuals diagnosed with mild cognitive impairment or AD. Results show relationships exist between membrane protein clustering characteristics and performance on tests of cognitive function as well as depressive symptoms. The results of membrane protein clustering in mild cognitive impairment and AD warrants further evaluation of membrane protein clustering in disorders marked by dysregulation of Reelin signaling. | |
| dc.description.embargo | 2025-12-31 | |
| dc.description.scholarlevel | Graduate | |
| dc.identifier.bibliographicCitation | Reive, B.S., Johnston, J., Sanchez-Lafuente, C.L., Scheil, K. et al. (2024) Intravenous Reelin rescues despair-like behaviour, Reelin cells in the dentate sub-granular zone, and spleen atrophy in the cyclic corticosterone model of recurring depressive episodes. Frontiers in Pharmacology, 15, 1368620. https://doi.org/10.3389/fphar.2024.1368620 | |
| dc.identifier.bibliographicCitation | Reive, B. S., Johnston, J. N., Sánchez-Lafuente, C. L., Zhang, L. et al. (2023) Intravenous Reelin Treatment Rescues Atrophy of Spleen White Pulp and Correlates to Rescue of Forced Swim Test Immobility and Neurochemical Alterations Induced by Chronic Stress. Chronic Stress, 7, 24705470231164920. https://doi.org/10.1177/24705470231164920 | |
| dc.identifier.bibliographicCitation | Reive, B.S., Lau, V., Sanchez-Lafuente, C.L., Henri-Bhargava, A. et al. (2024) The inflammation-induced dysregulation of Reelin homeostasis hypothesis of Alzheimer’s disease. Journal of Alzheimer’s Disease, 100(4), 1099-1119. https://doi.org/10.3233/JAD-240088 | |
| dc.identifier.uri | https://hdl.handle.net/1828/20971 | |
| dc.language | English | eng |
| dc.language.iso | en | |
| dc.rights | Available to the World Wide Web | |
| dc.subject | Neuroscience | |
| dc.subject | Depression | |
| dc.subject | Reelin | |
| dc.subject | Inflammation | |
| dc.subject | Antidepressant | |
| dc.subject | Alzheimer's disease | |
| dc.title | Reelin, stress, and inflammation: Implications for treatment of major depression and diagnosis of Alzheimer’s disease | |
| dc.type | Thesis |