Abstract:

Amyloid-β (Aβ) oligomers are a major cause of neurodegeneration in Alzheimer’s disease (AD). These soluble aggregates have proven difficult to isolate and study due to their inherent metastability and heterogeneity, but evidence has shown that toxic oligomers of Aβ are often composed of molecules of Aβ folded in β-hairpin conformations. The Nowick Laboratory has developed a peptide model system to study β-hairpins and elucidate high-resolution structures of the oligomers they form. In this defense, I will discuss how I have utilized this model system and human iPSC-derived neurons to understand the role of β-hairpins in Aβ oligomer formation and toxicity.  My research demonstrates that the alignment of the β-hairpin directs oligomerization and that the resulting oligomers exhibit varied biological properties depending on their structure. My research has further utilized an antibody developed against one of our oligomer models to study the relevance of this structure as a model of Aβ oligomers. I show that at sub-stoichiometric ratios, this antibody prevents Aβ42-mediated toxicity in human iPSC-derived neurons, suggesting that toxic oligomers of Aβ42 share structural similarities with our β-hairpin oligomer model. After covering my Ph.D. research, I will briefly discuss the work I did as a bioanalytical intern at AbbVie to quantify hydrolytic enzymes in the human vitreous humor using an LC/MS-MS based targeted proteomics workflow.