Engineering Amyloid Polypeptide Interactions Relating to Neurodegenerative Disease and Bio Material

The objective of this work was to engineer beta-amyloid (Abeta) peptides implicated in Alzheimer's disease (AD) to uncover mechanisms in neurodegenerative disease pathology and develop novel tools for controlled self-assembly of amyloid fibrils. In the first project, I studied Abeta interactions with another amyloid protein, alpha-synuclein (alphaS), which is implicated in Parkinson's disease (PD). Uncovering protein interactions between Abeta and alphaS is important due to the overlap of symptoms seen in AD and PD patients, as well as evidence linking the two pathologies. To achieve this, monomers, oligomers, and fibrils of both Abeta and alphaS were prepared and co-incubated to study their interactions. Abeta and alphaS were conjugated with fluorophores to track their locations within resulting co-assemblies more closely, along with other characterization techniques. This study revealed that alphaS inhibits Abeta fibrillization and stabilizes oligomerization through the Abeta C-terminus. In a second project, I engineered a dual Abeta-variant self-assembly peptide system for the precise control of amyloid assembly, for potential use in the study of size-dependent neurotoxicity and precise fabrication of amyloid biomaterials. The peptides are derived from the hydrophobic central domain of the Abeta peptide, and they are unique in that alone they do not self-assemble but hetero-assemble in the presence of their assembly partner to form amyloid fibrils similar to those formed by Abeta itself. By engineering the peptide termini and optimizing buffer conditions, the assemblies can also be modulated by balancing electrostatic and hydrophobic interactions. Overall, my PhD study reveals that interactions between different species of amyloid peptides can alter aggregation pathways and structures, also paving the way for many novel research applications.