SOLVENT EFFECTS ON SELF-ASSEMBLY OF BETA-AMYLOID PEPTIDE

beta-amyloid peptide (A beta) is the primary protein component of seni le plaques in Alzheimer's disease patients. Synthetic A beta spontaneo usly assembles into amyloid fibrils and is neurotoxic to cortical cult ures. Neurotoxicity has been associated with the degree of peptide agg regation, yet the mechanism of assembly of A beta into amyloid fibrils is poorly understood. In this work, A beta was dissolved in several d ifferent solvents commonly used in neurotoxicity assays. In pure dimet hylsulfoxide (DMSO), A beta had no detectable beta-sheet content; in 0 .1% trifluoroacetate, the peptide contained one-third beta-sheet; and in 35% acetonitrile/0.1% trifluoroacetate, A beta was two-thirds beta- sheet, equivalent to the fibrillar peptide in physiological buffer. St ock solutions of peptide were diluted into phosphate-buffered saline, and fibril growth was followed by static and dynamic light scattering. The growth rate was substantially faster when the peptide was prediss olved in 35% acetonitrile/0.1% trifluoroacetate than in 0.1% trifluoro acetate, 10% DMSO, or 100% DMSO. Differences in growth rate were attri buted to changes in the secondary structure of the peptide in the stoc k solvent. These results suggest that formation of an intermediate wit h a high beta-sheet content is a controlling step in A beta self-assem bly.