Document Type



Doctor of Philosophy



Date of Defense


Graduate Advisor

Michael R. Nichols, PhD


Dr Fung Hung-Gay

Keith J. Stine,PhD

Chung F. Wong, PhD


Alzheimer’s disease (AD) is a slowly progressing neurodegenerative disease that leads to dementia. Histopathological hallmarks that characterize AD are senile plaques formed by extracellular deposition of Amyloid beta (Aβ) peptide and intracellular aggregates of hyperphosphorylated tau protein. The plaques, which are found in the brain parenchyma, comprise both 40 and 42 residue Aβ. Aggregation of Aβ is an established pathogenic mechanism in AD, but little is known about the initiation of this process in vivo. Several studies have revealed significant inflammatory markers such as activated microglia and cytokines surrounding the plaques. Plaques are a hallmark of AD, but they are only part of an array of Aβ aggregate morphologies observed in vivo. Structural polymorphism is a prominent feature of Aβ aggregation both in vitro and in vivo. The molecular relationship between the different forms of Aβ remains to be determined. Inflammatory processes are believed to contribute to AD pathophysiology, and may play an important role in the disease progression. Not all Aβ deposits evoke a proinflammatory response, making it all the more important to probe into structural details of the Aβ aggregation pathway. This research was aimed at investigating what Aβ morphology or aggregation species induce the strongest proinflammatory response in human THP-1 monocytes as a model system. Our results indicate that an intermediate fibrillar aggregation species formed when Aβ(1-42) is reconstituted in water (100 μM, pH 3.6) and incubated at 4oC under quiescent conditions was capable of stimulating maximum tumor necrosis factor alpha (TNFα). Modulating conditions that accelerated or increased Aβ(1-42) fibril formation such as temperature, peptide concentration, or pH diminished the ability to activate the cells. Immunodepletion of Aβ(1-42) solution with fibril specific antibody (OC immune serum) reduced the ability to induce TNFα production. Characterization by SEC showed an included peak that appeared immediately after the void volume and stimulated the maximum proinflammatory response. We have also shown that the shorter peptide Aβ(1-40) could not stimulate a proinflammatory response under similar aggregation conditions. Overall, the data suggest that an intermediate Aβ(1-42) fibrillar precursor species is optimal for inducing maximum proinflammatory activity in THP-1 monocytes.

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