Date of Award

1-1-2012

Document Type

Campus Access Dissertation

Department

Chemical Engineering

First Advisor

Melissa A Moss

Abstract

Alzheimer's disease (AD) is the most common form of dementia and is characterized by brains that have developed extracellular plaques and intracellular tangles. The extracellular plaques are composed of aggregated amyloid-β protein (Aβ), which is widely believed to be the underlying cause of the disease. Mounting evidence suggests the small, soluble aggregates of Aβ induce the progressive neurodegeneration observed in AD patients. AD patients also display varying degrees of cerebrovascular pathology including the deposition of Aβ within vessel walls known as cerebral amyloid angiopathy (CAA). The prevalence of CAA and of dementia caused directly by vascular damage supports the idea that cognitive impairment arises from a blend of vascular and neurological changes. Furthermore, similar cellular dysfunctions observed in the vasculature and brain, such as inflammation, suggest that a common element in cerebrovascular and neuronal cells mediates disease progression. With its significant role in inflammatory responses, the nuclear factor-κB (NF-κB) pathway is hypothesized to play such a regulatory function in AD.

The work presented here examines the cellular activation of NF-κB by Aβ aggregates in both cerebrovascular and neuronal cells. Small Aβ aggregates isolated by size exclusion chromatography activate NF-κB at physiological concentrations while unaggregated Aβ monomer and large Aβ aggregates do not. Activation of this pathway in cerebrovascular cell monolayers mediates increased permeability and increased adhesion of monocytes, two phenotypic changes characteristic of AD. In addition, the results demonstrate Aβ aggregates reduced in size by flavonoids induce a less pronounced activation of NF-κB in neuronal cells. Flavonoids are the most abundant polyphenolic compounds found in the human diet, and the structure of polyphenolic compounds enables them to effectively inhibit Aβ aggregation. By taking advantage of differences in diets between cultures, epidemiological studies have established a correlation between the increased intake of flavonoids and reduced incidence of AD. The results from this work validate, on a molecular and cellular level, the idea that flavonoids can mitigate the pathogenic effects of Aβ that lead to AD.

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