Date Available

3-28-2017

Year of Publication

2017

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Physiology

First Advisor

Dr. Donna M. Wilcock

Abstract

It was once believed that the brain was immunologically privileged with no resident or infiltrating immune cells; 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 and dementia (VCID); however, the role of inflammation in these two dementias is poorly understood.

When we stimulated a pro-inflammatory phenotype with an adeno-associated viral vector in a transgenic mouse model of AD that develops Aβ 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 Aβ burden suggesting that anti-inflammatory markers contribute to disease progression.

Treatment of astrocytes, microglia, endothelial cells and neurons with high levels of homocysteine, a risk factor for VCID, resulted in a wide range of gene expression changes. 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 affect tau phosphorylation.

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.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2017.051

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