Structure/Function Analysis of A-beta Fibril Assembly

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DESCRIPTION (Provided by applicant): Amyloid fibrils and other ordered aggregation products of the Alzheimer's plaque peptide A-beta have been implicated by genetic, pathological, and cell culture studies to have a role in the development of Alzheimer's disease. Strategies targeting the growth or toxicity of these aggregates are formally possible but technically difficult owing in part to our ignorance of both fibril structure and of fibril assembly pathways and energetics. In this grant application we propose to implement new strategies to obtain information on structure and assembly, which will contribute, for example, to both the design and testing of inhibitors of fibril formation. We will utilize scanning mutagenesis linked to a number of in vitro assays for fibril growth to dissect the roles of key amino acid residue positions of A-beta in fibril formation and stability. We will use surface plasmon resonance (SPR) to study details of the kinetics of fibril assembly and disassembly with both wild type and mutant A-beta sequences.