Identifying Aggregation-Prone and Aggregation-Resistant Conformations of Amyloid Beta

In this work we build a formalism for modeling the thermodynamics of IDPs and apply these methods to construct unfoled ensembles for small soluble oligomers of Amyloid-Beta (Aβ) that have been implicated in the pathogenesis of Alzheimer’s disease. The specific aims of this proposal are to: 1) Build structural models for Aβ variants and use these data to identify potential aggregation-prone and aggregation-resistant conformations; 2) Generate solutions enriched in aggregation-prone and aggregation-resistant conformations of Aβ using a disulfide-scrambling assay. The aggregation potential of these solutions will be tested in vitro; 3) Develop models for soluble oligomeric states of wild-type Aβ and mutants associated with different aggregation rates. We use these data to find structural features in soluble oligomers that are associated with increased toxicity.  We believe these data provide an unprecedented view of the relationship between sequence, structure, and toxicity of Aβ.