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There is now a CONTENT FREEZE for Mercury while we switch to a new platform. It began on Friday, March 10 at 6pm and will end on Wednesday, March 15 at noon. No new content can be created during this time, but all material in the system as of the beginning of the freeze will be migrated to the new platform, including users and groups. Functionally the new site is identical to the old one. webteam@gatech.edu
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Advisor:
Levi B. Wood, Ph.D. (Georgia Institute of Technology, School of Mechanical Engineering)
Thesis Committee:
Young Jang, Ph.D. (Georgia Institute of Technology, School of Biological Sciences)
Tony Kim, Ph.D. (Georgia Institute of Technology, School of Mechanical Engineering)
Effects of Neuorinflammation on Vascular Dysfunction in Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 35 million people worldwide, and lacks any effective therapy to stop or slow the disease. AD is characterized by progressive appearance of extracellular amyloid beta (Aβ) plaques in affected regions of the brain, which lead to neuronal dystrophy and death. There is increasing evidence, however, that Aβ is not the sole driver of disease progression. A functional MRI study has revealed that the blood-brain barrier (BBB), a vital regulator of molecular transport between the brain and vascular system comprised in part of microvascular endothelial cells, becomes leaky early in disease. Furthermore, analysis of postmortem tissue has revealed reduced angiogenic vascular growth in AD tissues. Thus, vascular defects may promote neuronal death by reducing perfusion and allowing peripheral cells to enter the brain. The mechanisms responsible for BBB breakdown have not been delineated, but may be influenced or driven by Aβ and neuroinflammation. Inflammatory cytokines such as tumor necrosis factor alpha (TNFα) have been previously established by our lab and others to be upregulated in the AD microenvironment. I hypothesize that Aβ and inflammatory cytokines together drive loss of vascular endothelial barrier function and angiogenic sprouting. To test this hypothesis, I have used an integrated cell culture approach combining transwell plates, 2D cell cultures, and 3D microfluidic devices. Dextran permeability assays in microfluidics and transwell plates demonstrate that Aβ conditions increase endothelial permeability. Further, western blotting of 2D cultures demonstrates a dose-dependent down-regulation of both platelet-endothelial cell adhesion molecule (PECAM) and VE-cadherin expression in response to Aβ. Since PECAM is a critical regulator of angiogenesis, I quantified changes in angiogenic sprouting in response to Aβ using our microfluidic platform, thus in total my data will link PECAM dysregulation to dual vascular pathologies in AD: loss of barrier function and reduced angiogenic growth. In total, my data demonstrate that Aβ and key AD cytokines effect endothelial barrier function and angiogenic sprouting. Moreover, my approach combining 2D and physiologically relevant 3D cell cultures provides great utility for interrogating vascular response to specific components of the AD microenvironment.
