Date of Award

Summer 5-15-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

School

Mathematics and Natural Sciences

Committee Chair

Vijay Rangachari

Committee Chair School

Mathematics and Natural Sciences

Committee Member 2

Faqing Huang

Committee Member 2 School

Mathematics and Natural Sciences

Committee Member 3

Jacques Kessl

Committee Member 3 School

Mathematics and Natural Sciences

Committee Member 4

Hao Xu

Committee Member 4 School

Biological, Environmental, and Earth Sciences

Committee Member 5

Preetam Ghosh

Abstract

Deposition of extracellular proteinaceous plaques of amyloid-β (Aβ) is one of the major hallmarks of Alzheimer disease (AD). Although, insoluble high molecular fibrils of Aβ are the main constituents of the senile plaques in AD, low molecular weight soluble Aβ oligomers have emerged as the key toxic species involved in memory impairment and neuronal cell death in AD. The process for generation of oligomers can be highly diverse and can involve homotypic interactions of Aβ as well as heterotypic interaction of Aβ with other macromolecules. Previously, the generation of Aβ oligomers with distinct biochemical and biophysical characteristics catalyzed non-esterified fatty acid micelles (large fatty acid derived oligomers (LFAO)) was observed by our lab. In the work presented here the generation of Aβ oligomer strains have been demonstrated in the presence of lyso-phospholipid micelles of different chain lengths and gangliosides with different sugar distributions in their head groups. It has been shown that lipids of different characteristics can assist the generation of biophysically distinct oligomers with differences in toxicity in AD brains. We also furthered this study to investigate oligomerization of Aβ in liposomal model membrane systems with varied lipid composition and found GM1 as a key mediator in Aβ oligomerization and its cooperative membrane damage. Lastly, this work reveals that Aβ oligomerization by gangliosides is mediated by their sugar distribution and positively charged amino-acid in the N-terminal region of Aβ. Overall, this study brings forth molecular insights of key components responsible for oligomer strain generation and hence propagation of disease in the AD pathology.

Available for download on Tuesday, June 10, 2025

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