Date of Award

Spring 2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

School

Polymer Science and Engineering

Committee Chair

Sarah E. Morgan

Committee Chair School

Polymer Science and Engineering

Committee Member 2

Robert L Lochhead

Committee Member 2 School

Polymer Science and Engineering

Committee Member 3

Sergei Nazarenko

Committee Member 3 School

Polymer Science and Engineering

Committee Member 4

Derek L. Patton

Committee Member 4 School

Polymer Science and Engineering

Committee Member 5

Vijayaraghavan Rangachari

Committee Member 5 School

Mathematics and Natural Sciences

Abstract

Aggregation and subsequent deposition of amyloid-β (Aβ) peptide on neuronal cell membranes have been implicated as a cause of Alzheimer’s disease. Gangliosides in their clustered form seed and promote the Aβ aggregation process. However, the effects of the structure and the concentration of ganglioside saccharides on Aβ aggregation are not well understood. We investigated how the specific structure of saccharides (β-D-galactose and β-D-glucose) affect the aggregation pathways, kinetics, and the aggregated structures of Aβ via in vitro experiments. The effects of the local concentration of saccharides on the Aβ aggregation were also investigated.

To mimic the multivalent effect of the ganglioside saccharides, we designed and synthesized stereospecific bio-relevant saccharide containing model polymers, known as glycopolymers in solution and from surfaces. Acrylamide based glycopolymers of desired molecular weights were synthesized in solution via reversible addition-fragmentation chain transfer (RAFT) polymerization. Using thioflavin T fluorescence (ThT) and polyacrylamide gel electrophoresis (PAGE), we found that the Aβ formed small aggregates in the presence of high molecular weight (DP 350) glucose containing polymers, but large aggregates were formed in the presence of low (DP 35) molecular weight glucose containing polymers, low and high molecular weight galactose containing polymers, and non-saccharide control polymers.

Glycopolymer films of high and low thickness were synthesized from silicon surfaces via photopolymerization and surface-initiated RAFT polymerization and the effect of the saccharides of grafted glycopolymers on Aβ aggregation were investigated. Quartz crystal microbalance (QCM)experiments established that the Aβ bound more strongly with the glucose polymer grafted surfaces than the galactose polymer grafted surfaces. AFM imaging revealed that the Aβ aggregated to form fibrils when incubated with the thin films of glucose or galactose polymers and control surfaces.

These results suggest that the high molecular weight glucose-containing polymers strongly affect and alter the Aβ aggregation pathway and promote the formation of Aβ oligomers while other polymers do not affect the aggregation process.

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