PhD ThesisMetabolic disorders induce a low-grade chronic inflammatory state that is damaging to the peripheral vasculature, leading to cardiovascular diseases. In recent years, there has been mounting evidence linking metabolic disease to neurovascular disorders and cognitive decline. However, the pathophysiological response occurring at the brain microvasculature, the blood-brain barrier (BBB), remains largely unexplored.
Using a mouse model of Type II diabetes mellitus, the results of this project demonstrate pro-inflammatory mediators and altered immune responses to impair the protective BBB functionality. Disruption to tight junctions and basal lamina, due to loss of control in activation/production of MMPs and their inhibitors, causes complete BBB breakdown. Metabolic stress triggers endothelial dysfunction resulting in altered metabolism and receptor expression, enhanced ROS production and up-regulated adhesion molecules. Immunologically, there is an increase in the percentage of activated effector and central memory T-cells along with an imbalance in the TH17/Treg subsets. Together these factors augment transmigration of leukocytes across the BBB to trigger activation and shift of microglia to a pro-inflammatory phenotype, initiating neuroinflammation. Loss of the physical, transport and metabolic properties of the BBB will consequently have detrimental effects on neuronal function.
Additionally, this thesis explores the use of a pharmacological and dietary intervention to reduce and restore the damage incurred to the BBB. Treatment with human recombinant annexin A1 (a well know anti-inflammatory molecule) and reversion from a high-fat high-sugar diet to a chow diet both attenuate T2DM development, reduce peripheral inflammation and dampen the immune response, resulting in restored BBB integrity. Both interventions confer neuroprotection through stabilisation of cell-cell contacts, consequently limiting leukocyte extravasation and downstream pathological events.
This thesis emphasises the growing understanding of long-term impact of metabolic disease and their contribution to the development of neuroinflammatory/ neurodegenerative disorders. Preventive and therapeutic strategies that mediate anti-inflammatory effects are key in limiting the disease progression
