Investigation of amyloid polymorphism and its role in Alzheimer's disease pathogenesis
Amyloid fibrils are insoluble protein aggregates with a broad range of biophysical properties and biological functions. Potentially all proteins can form amyloids, each of which can adopt a multitude of distinct molecular conformations, or polymorphs. Characterizing the molecular structure of various polymorphs and linking these features to their function or pathology is a prevalent challenge across biology, medicine, and technology. In this dissertation, I explore multiple aspects of amyloid structure and its relationship to biology. In Chapter 1, I work towards expanding a fluorogenic dye toolkit that can report on structural differences among amyloids; determining the structural composition of fibrils generated from multiple distinct species of amyloid beta (Aβ); and interrogating the atomic connections governing a functional amyloid’s macrostructure. In Chapter 2, I investigate the prevalence of different species of Aβ along the trajectory of Alzheimer’s disease (AD) pathology in Down syndrome (DS). In the latter work, I find that different subsets of Aβ may predominate in the brain tissue of people with early compared to advanced AD pathology and that a more heterogeneous population of Aβ species are present at the late stages of disease in DS.