Date of Graduation
School of Medicine
James W. Simpkins
Candice M. Brown
Candice M. Brown
Werner J. Geldenhuys
Inflammation within the central nervous system (CNS), termed neuroinflammation, is a defining characteristic of many neuropathological conditions, including Alzheimer’s disease (AD) and stroke. Certain inflammatory mediators activate the transcription factor NF-κB, which induces transcription of many pro-inflammatory genes, including miR-34a and miR-146a. Several target candidate genes of these miRNAs encode for proteins of the mitochondrial electron transport chain. In our studies, we demonstrate that in response to inflammatory stimuli, such as TNF-α, the expression of miR-34a and -146a is significantly increased in several CNS cell types, and in their secreted extracellular vesicles (EVs). Exposure to TNF-α-derived EVs significantly increases cellular bioenergetics in naïve recipient cells, with a concurrent increase in reactive oxygen species, indicative of impaired mitochondrial function. Further, using an animal model of experimental transient middle cerebral artery occlusion, we assess the effects of intermittent systemic LPS exposure, with long recovery periods, on stroke infarct volume. Relative to saline controls, animals repeatedly exposed to LPS have significantly larger cortical infarcts, and lower mRNA expression of autophagy genes. Inflammation-induced reduction in autophagy may lead to post-stroke increases in apoptosis. Together, these data suggest that the modulation of miR-146a and miR-34a in response to neuroinflammatory stimuli may mediate the loss of mitochondrial integrity and function of cells, and that EVs significantly impair mitochondrial function in recipient cells. Further, intermittent systemic inflammation significantly alters the neuroinflammatory response within the brain, leading to increased stroke infarct volumes.
Russell, Ashley E., "Role of Extracellular Vesicles in Neuroinflammatory Progression and Mitochondrial Functional Alterations" (2019). Graduate Theses, Dissertations, and Problem Reports. 3947.
Available for download on Friday, January 22, 2021