P2 - ABSTRACT The misfolding and aggregation cascade of the A? polypeptide is widely accepted to be the root cause of Alzheimer's disease (AD). However, the development of agents that are able to alter the misfolding and aggregation cascade has proven difficult. Small molecules are generally unable to present sufficiently large interaction surfaces to compete with the protein-protein interactions that drive aggregation, while antibodies are difficult to direct against specific conformational or oligomeric states. An alternative is the rational, computer- aided design of proteins and peptides that are able to bind specifically to particular species in the A? misfolding and aggregation cascade, and which can alter this process in well-defined ways. We propose to develop agents able to alter A? misfolding and aggregation in three ways, each representing a different possible strategy for mitigating A? neurotoxicity. First, we will create small proteins that are able to bind specifically to monomeric A? that has not yet entered the aggregation cascade, sequestering it or directing it for clearance or degradation. Second, we will create peptides able to cap growing A? amyloid fibrils to block fibril elongation, shifting the A? population to soluble species that can be cleared by other mechanisms. And third, we will create fibril-coating proteins that are able to stabilize pre-formed A? amyloid fibrils and prevent the dissociation that can produce toxic, soluble, oligomeric species. The peptides and proteins produced will be useful experimental agents for testing different AD treatment strategies, based on several different hypotheses of A? toxicity, in model systems.
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