Date of Award

Spring 2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

School

Mathematics and Natural Sciences

Committee Chair

Vijay Rangachari

Committee Chair Department

Chemistry and Biochemistry

Committee Member 2

Douglas Masterson

Committee Member 2 Department

Chemistry and Biochemistry

Committee Member 3

Jacques Kessl

Committee Member 3 Department

Chemistry and Biochemistry

Committee Member 4

Faqing Huang

Committee Member 4 Department

Chemistry and Biochemistry

Committee Member 5

Sarah Morgan

Committee Member 5 Department

Polymers and High Performance Materials

Abstract

Alzheimer disease (AD) is a fatal neurodegenerative disorder characterized by the widespread deposition of proteinaceous plaques abundant in amyloid-β (Aβ) aggregates. Although the plaques mainly contain high molecular weight, insoluble Aβ fibrils, the low molecular weight soluble aggregates called oligomers have been shown as the primary toxic species responsible for synaptic dysfunction and neuronal loss in AD. The process of aggregation is nucleation-dependent, but also highly stochastic and inhomogeneous resulting in biophysically diverse assemblies. Recent advances in the field indicate a potential correlation between the phenotypic diversity observed in AD subtypes and aggregate polymorphism. Therefore, understanding the molecular mechanisms which lead to the generation of diverse Aβ oligomer structures (strains), and their subsequent propagation to polymorphic fibrils is crucial in establishing structure-phenotype correlations in AD. Our laboratory has previously characterized a specific Aβ oligomer called large fatty acid-derived oligomers (LFAOs), generated in the presence of fatty acid micelles. The work presented here has two main objectives: i) to determine the biophysical and biochemical properties of LFAOs in the context of strain behavior, particularly in the propagation of their structure; and ii) to determine the mechanism of oligomer strain generation by a family of lipids that are known to interact with Aβ. This work details the mechanism of LFAO strain propagation, which occurs in three distinctive phases involving a key intermediate. Also detailed is how LFAOs affect neuronal cells and selectively induce cerebral amyloid angiopathy (CAA) in transgenic AD mice brains, cementing the idea that distinct oligomer strains can influence AD phenotypes. Lastly, this work reveals that a family of Aβ oligomer strains can be generated in interfacial conditions, suggesting that lipids present in the AD brain may play a role in strain generation. Overall, this brings forth fundamental mechanistic paradigms involved in oligomer strain generation and propagation that has invoked substantial insights into AD pathology.

ORCID ID

0000-0002-2279-3393

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