Student Successfully Defends Dissertation

On Tuesday, March 7th Physiology trainee Erica Weekman successfully defended her dissertation and earned her doctoral degree.

"Neuroinflammation in Alzheimer’s disease and vascular cognitive impairment"

Doctoral Committee Members 
Dr. Donna Wilcock
Department of Physiology, Mentor

Dr. Steve Estus
Department of Physiology

Dr. Elizabeth Head
Department of Pharmacology & Nutritional Sciences

Dr. Joe Abisambra
Department of Physiology

Dr. Chris Norris
Department of Pharmacology & Nutritional Sciences

Outside Examiner
Dr. Nada Porter
Department of Pharmacology & Nutritional Sciences

Abstract of Dissertation
It was once believed that the brain was immunologically privileged due to the blood brain barrier; however, now it is understood that the cells of the brain are capable of a wide range of inflammatory processes and phenotypes. Inflammation in the brain has been implicated in several disease processes such as Alzheimer’s disease (AD) and vascular cognitive impairment (VCID). The role of inflammation in these two dementias is poorly understood though.

When we stimulated a pro-inflammatory phenotype with an adeno-associated viral vector in a transgenic mouse model of AD that develops amyloid plaques, we saw a pro-inflammatory response at 4 months that transitioned to a mixed phenotype by 6 months. This transition also appeared with an increase in amyloid burden suggesting that anti-inflammatory markers contribute to disease progression.

Treatment of astrocytes, microglia, endothelial cells and neurons with homocysteine, a risk factor for VCID, resulted in a wide range of gene expression changes in each cell type. Astrocytes showed decreased levels of several potassium channels and aquaporin 4 and increased matrix metalloproteinase 9. Microglia showed an initial pro-inflammatory response that transitioned to an anti-inflammatory phenotype. Endothelial cells showed a disruption in several tight junction proteins and neurons had changes in kinases and phosphatases known to phosphorylate tau.

Finally, while AD and VCID are the two most common forms of dementia, they are not mutually exclusive and it is estimated that 60% of AD patients also have cerebrovascular pathology contributing to the clinical syndrome. To determine the effect of co-morbid AD and VCID on the effectiveness of therapies that target AD pathologies, we placed APP/PS1 mice on a diet that induces hyperhomocysteinemia and consequently VCID. These mice were then placed on an anti-Aβ immunotherapy. While the co-morbidity mice had a significant reduction in Aβ, there was no cognitive benefit of the immunotherapy in these mice. Interestingly, these co-morbidity mice also had a reduction in inflammatory markers and microglial staining, suggesting a suppressed inflammatory response.

From these studies, it is clear that inflammation plays a complex role in AD, VCID, and during treatment when both AD and VCID are present.

First and foremost, I’d like to thank my mentor, Donna Wilcock, for giving me the opportunity to do my graduate research in her lab. She has shown me how to be a successful woman in science and her guidance, patience and support have shaped me into the scientist I am today. I could not have asked for a better mentor. Thank you.

Even though her ridiculous level of productivity made the rest of us in the lab look bad, I also have to thank our lab manager, Tiffany Lee. She taught me almost every lab technique I know and dealt with the multitude of questions I’ve had over the last 5 years.

I’d also like to thank each of my committee members, Steve Estus, Elizabeth Head, Jose Abisambra and Chris Norris, for their expertise, critiques and ideas regarding my project.
Finally, I wouldn’t be here today without my family. Their love and encouragement mean everything and I’m grateful that they’ve always been there for me.