Conformational transition of soluble monomeric amyloid beta-peptide (Abeta) into oligomeric and protofibrillar aggregates plays a key role in the pathogenesis of Alzheimer's disease (AD). One of the central questions surrounding the molecular pathophysiology of AD is how the soluble Abeta is converted into its aggregated toxic form. A more detailed understanding of the conformational transitions involved in the self-assembly of Abeta may facilitate the design of inhibitors of aggregation. In this study, we evaluated the wild-type (WT) Abeta 16-28 peptide (KLVFFAEDVGSNK) and its associated mutants, including A21G (Flemish), E22K (Italian), E22Q (Dutch), and E22G (Arctic) mutants, by examining, in particular, their aggregation kinetics in the presence and in the absence of negatively charged and zwitterionic lipids. Circular dichroic and thioflavin T fluorescence studies indicated that the WT peptide undergoes a rapid conformational transition into beta-sheet structure in solution, whereas the Arctic and Dutch variants show a markedly rapid transition into beta-sheet structure in the presence of negatively charged lipids. These results provide strong evidence suggesting that the reduction in net charge, with a concurrent increase in the net hydrophobicity of the peptide alone or when complexed with lipid in solution, determines the rate of aggregate formation.

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