Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry, Biochemistry

Date of Defense

7-22-2022

Graduate Advisor

Michael R. Nichols

Committee

Michael R. Nichols (Chairperson)

Keith J. Stine

Chung F. Wong

Alexei V. Demchenko

Abstract

Misfolded protein aggregates are one of the significant contributing factors in many neurogenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and others. My PhD research project was to study various aspects of amyloid-β peptide, a 40-42-residue peptide and the primary component of the senile plaques found in Alzheimer’s disease (AD) brains. One objective of my research was to purify and characterize the intermediate Aβ42 species using an array of biophysical techniques like size exclusion chromatography, fluorescence assays, circular dichroism, cellular assays, and protein assays. The other major research thrust of my project was to study the role of microglial cell derived extracellular vesicles in the aggregation of Aβ42. Isolation of extracellular vesicles with Aβ42 protofibrils from the primary microglial cells or BV-2 microglial cells and their characterization with dynamic light scattering, NBD fluorescence, flow cytometry, and microscopy techniques enabled to explore the effect of these vesicles in Aβ aggregation. Neuroinflammation is another important aspect of AD pathology. So, I was involved in the screening of several lipid A based organic compounds to study their potential to antagonize the release of inflammatory cytokine, TNF-α, induced by TLR4 ligands. We have identified and established the structure-activity relationship of the effective antagonists.

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