Characterising changes to the Blood-Brain Barrier in Healthy Ageing and Following Stroke in an Aged Preclinical Model
| dc.contributor.advisor | Turner, Renée | |
| dc.contributor.advisor | Collins-Praino, Lyndsey | |
| dc.contributor.advisor | Hood, Rebecca | |
| dc.contributor.author | Bilecki, Isabella M | |
| dc.contributor.school | School of Biomedicine | |
| dc.date.issued | 2024 | |
| dc.description.abstract | The ageing population is set to surpass 2.1 billion people by 2050. Importantly, age is the most predominant non-modifiable risk factor increasing the prevalence of ischaemic stroke and a strong predictor of poor stroke outcome. Currently more than 77 million people worldwide are living with consequences of ischaemic stroke; and of these 77 million, ~39% are over 70 years of age. This places significant growing burden on health care systems and highlights a significant need for identifying pathological targets areas for improved post-stroke intervention. Most preclinical research conducted in the stroke field use young and otherwise healthy animals, with less than 1% incorporating age and/or relevant comorbidities. Subsequently, studies often neglect to consider the influence of age on stroke pathogenesis and mechanisms that drive post-stroke neurological decline. One such pathological process observed following stroke is the disruption of the blood-brain barrier (BBB). Notably, the integrity of the BBB also declines in the setting of normal physiological ageing. In both ageing and following stroke, the BBB becomes leaky due to the loss of paracellular tight junction (TJ) proteins which are vital for creating a near impermeable barrier between adjacent brain vascular endothelial cells (BVECs), and an increase in transcellular transport processes (namely caveola) allowing transcytosis of vesicles across BVECs. In addition to the direct changes resulting in unregulated transport across the BBB, alterations to other BBB support cells and structures (such as the basement membrane (BM) and astrocytes) have also been implicated in ageing and following stroke. However, the investigation of changes to the BBB in the aged preclinical cohort following stroke is currently lacking in the literature. As such, the focus of this thesis is to explore the implications and outcomes of age on post-stroke changes to the BBB and functional outcome. To do so, we utilised a cohort of young (n=26; 3-months) and aged rats (n=244; 12–18-months at stroke onset) across six studies to assess changes to the BBB with advancing age, determine alterations to BBB structure and permeability following stroke in an aged brain, assess functional outcomes that are influenced by stroke in the aged brain out to 28-days, and to outline the challenges associated with working with an aged rodent cohort. Here we demonstrate significant extravasation of blood proteins (albumin and IgG) in the aged brain and following stroke in the setting of age, not only in the peri-infarct region but also in remote neuroanatomical areas. Subsequently, we demonstrate that age and stroke increase expression of caveolin-1 (a marker of transcytosis), claudin 5 (TJ protein) and collagen IV (BM protein). Furthermore, the thesis findings highlight that working with aged animals significantly differs from young adult animals, with respect to histological changes in the brain both pre- and post-stroke, management and heath care required to maintain a large, aged cohort and how functional outcome is assessed. This highlights the significance of incorporating sufficient age into study design when investigating therapeutics targeted at minimising ongoing pathological changes in the brain poststroke and associated neurological decline. | |
| dc.description.dissertation | Thesis (Ph.D.) -- University of Adelaide, School of Biomedicine, 2024 | en |
| dc.identifier.uri | https://hdl.handle.net/2440/144050 | |
| dc.language.iso | en | |
| dc.provenance | This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals | en |
| dc.subject | stroke | |
| dc.subject | ageing | |
| dc.subject | blood-brain barrier | |
| dc.subject | preclinical | |
| dc.subject | rodent | |
| dc.title | Characterising changes to the Blood-Brain Barrier in Healthy Ageing and Following Stroke in an Aged Preclinical Model | |
| dc.type | Thesis | en |
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