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Abstract

Alzheimer’s Disease (AD) is a devastating neurological disorder that impacts millions of people around the world. There is strong evidence that the class of peptides, Amyloid-β, is causative in the neurodegeneration that takes place during AD. Amyloid-β peptides share a common trait, which is the ability to aggregate (or self-associate) to form higher-ordered structures. Of these structures, the mature fibrils act as a final product of this aggregation and are part of the neuritic plaques formed in advanced AD. Much is known about the mature fibrils in terms of their toxicity and molecular structure; however, in the past several decades it has been revealed that aggregate intermediates, such as small oligomers, are just as cytotoxic, if not more, compared to the mature fibril. However, there is very little know about the mechanism of aggregation and structure of these intermediates. In this thesis, I explore the critical role that amphilicity and heterogenous nucleation play in the production and stability of the aggregation intermediates. In Chapter 2, we tested the hypothesis that Aβ21-30 is a putative core domain that takes on structure to promote aggregation. However, we found that Aβ21-30 does not have any structure or aggregate. Therefore, we tested a new hypothesis that aggregation is driven by hydrophobic interactions. We appended hydrophobic residues to Aβ21-30 to make Aβ16-34 and found that it forms fibrils through the hydrophobic effect. We then added a cysteine to Aβ16-34 to replicate heterogeneous nucleation and found that the added ”focal point” resulted in faster aggregation. In Chapter 4, we explored the aggregation of full-length Aβ40 and the role of amphilicity in the formation of oligomers. We found that Aβ40 forms small, stable oligomers via hydrophobic residues in the C-terminal domain. These NanoDroplet Oligomers (NanDOs) are a flickering species that can associate with Zinc ions through the N-terminal domain to produce flocs.

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