Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Dr. Shawn N Whitehead

2nd Supervisor

Dr. Stephen H Pasternak

Co-Supervisor

Abstract

The white matter of the brain is an important site of age-related degeneration that can be exacerbated in neurological disease. White matter abnormalities can be visualized using magnetic resonance imaging (MRI) and appear as hyperintense regions called white matter hyperintensities (WMH). WMH are associated with increased risk of cognitive decline, dementia and mortality. Although blood brain barrier dysfunction and aberrant microglia signaling have been implicated in the pathophysiology of WMH, the relationship between these two phenomena remains unclear. The first aim of this thesis was to use post-mortem imaging methods in combination with histological data to investigate the relationship between evidence of WMH, tissue loss, BBB dysfunction and microglia activity. WMH are significantly associated with areas of increased blood brain barrier dysfunction evidenced by extravasation of fibrinogen and associated with increases in microglia. In vitro modelling demonstrated that fibrinogen upregulates pro-inflammatory signaling in microglia and leads to the release of extracellular vesicles (EVs) that propagate pro-inflammatory signaling to naïve cells. These findings shed light on possible mechanisms underlying the development of WMH and their detrimental effects on white matter structural integrity. Importantly, there exists few tools that allow for clinical measurement of BBB function or microglia activity, making it difficult to translate in vitro findings into meaningful clinical applications. The second aim of this thesis was to test whether extracellular vesicles released from microglia (MEVs) could serve as indicators of their phenotype and potential biomarkers in the future. Using in vitro models, it was confirmed that MEVs are reflective of microglia activation status. Next, in vivo experiments tested whether cargo and surface markers of circulating MEVs could indicate microglia activity in experimental models of stroke and Alzheimer’s disease. This represents the first work to our knowledge to demonstrate the non-invasive detection of MEVs specific to microglia phenotype. Future work is required to determine the association between MEVs, white matter disease and clinical outcomes.

Summary for Lay Audience

With the aging population and rise of dementia, there is a need for an improved understanding of early markers of cognitive decline. Current treatment strategies have been largely ineffective at treating later disease states. The need to identify and halt early disease progression is being increasingly recognized. White matter inflammation is one of the earliest changes that predicts future dementia and occurs years before significant memory impairment. My thesis work focused on understanding how white matter inflammation contributes to white matter disease and cognitive decline, and how this can be detected in healthy aging and neurological disease. Using cellular approaches, I sought to better understand the processes occurring within the aged white matter and the role of the brain’s inflammatory cells. Next, I studied profiles of proteins within the blood that are released by inflammatory cells in the brain. They are released into the blood within microparticles called extracellular vesicles. I studied microparticles in blood samples collected from experimental animal models of stroke and Alzheimer’s disease to identify proteins that indicate inflammation and dysfunction. Inflammation in the brain is an ideal target to study because it often precedes cognitive impairments and occurs in potentially treatable stages of disease. The outcome of this work will allow for the detection of microparticles that indicate the involvement of the brain inflammation, representing a novel blood-based screening tool that is applicable in multiple neurological diseases.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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