Characterising the Role of Neuroinflammation in Delayed Neurodegeneration Following Ischemic Stroke in a Long-Term Rodent Model
Date
2025
Authors
Stuckey, Shannon Mikayla
Editors
Advisors
Turner, Renée
Collins-Praino, Lyndsey
Hood, Rebecca
Collins-Praino, Lyndsey
Hood, Rebecca
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Thesis
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Abstract
With the implementation of acute stroke treatments such as mechanical thrombectomy and tissue plasminogen activator (tPA), we have vastly improved stroke survival rates. Whilst this is a cause to celebrate, it has brought to light a range of post-stroke complications. The number of strokes in younger individuals is also increasing, highlighting the growing number of years individuals are living with the consequences of stroke. Notably, the incidence of post-stroke cognitive impairment and dementia is steadily increasing. As such, there is a significant need to increase our understanding of long-term pathological processes driving these impairments to identify pathological targets for improved recovery. A leading pathology thought to contribute to cognitive decline, functional deficits and psychosocial impairments is secondary neurodegeneration (SND). SND encompasses heightened inflammation, neuronal loss and neurodegeneration (among others), in brain regions distal to the infarct. It is a delayed process, not commonly observed in patients until 1 month post-stroke, highlighting an increased therapeutic window. Regions such as the thalamus, hippocampus and basal ganglia are heavily implicated, likely due to their connections to the infarct. Both preclinical and clinical studies suggest neuroinflammation drives neuronal loss in these regions, with inflammatory changes occurring days before degeneration. Furthermore, at more chronic timepoints (3 – 7 months) microglia are colocalised with neurodegenerative proteins, displaying specific characteristics commonly noted in neurodegenerative diseases. These studies highlight the likelihood that targeting post-stroke neuroinflammation would be beneficial for improving patient outcomes. Nevertheless, neuroinflammatory treatments are still failing in the clinic. The exact reason for this is unknown; however, as many of these treatments are focused on the acute phase (< 2 weeks), they fail to account for long-term changes and SND specifically. Furthermore, whilst we have seen clear evidence of neuroinflammatory alterations driving degeneration in these distal regions, very little is known beyond that 7 month timepoint, with most studies conducted within the first 3 months and only one or two investigating beyond a year. As such, this thesis focuses on exploring the longterm neurodegenerative and neuroinflammatory alterations in regions of SND and the associated behavioural changes. To do so, we utilised a young rodent cohort (male Sprague-Dawley rats, n = 88, 3 months-old) and induced stroke or sham surgery before ageing them out to 12- and 15-months post-stroke. This allowed us to assess long-term changes associated with stroke and increasing age. Here, we demonstrate a significant interplay between stroke and age at chronic timepoints. Whilst we mainly saw expected stroke-related changes in the 12-month cohort, the 15-month cohort showed surprising interactions. Indeed, whilst increased functional impairment, anxiety-like behaviours and inflammatory alterations were evident at 12-months post-stroke, these changes were subsiding or completely attenuated in the 15-month stroke group. Notably, these changes were observed in conjunction with significant increases in inflammation and cognitive impairment with age, as seen in the 15-month sham group. Taken together these findings highlight, that stroke may alter the trajectory of age-related pathology. Whether this is indicative of post-stroke immunosuppression, inflammatory preconditioning or another mechanism, remains unclear. However, this thesis together highlights the importance of incorporating long-term timepoints and aged animals into preclinical stroke studies and emphasises the importance of investigating a wide range of distal regions due to regional specificity in some of the results. Finally, within this cohort, we were able to provide evidence for ongoing inflammatory alterations, highlighting its role in driving post-stroke SND and emphasising the importance of furthering our understanding of these mechanisms in the hope of identifying targets for therapeutic intervention to improve post-stroke complications and long-term recovery.
School/Discipline
School of Biomedicine
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Biomedicine, 2025
Provenance
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