Structural studies of soluble oligomers of the Alzheimer beta-amyloid peptide

Recent studies have suggested that non-fibrillar soluble forms of A beta pe ptides possess neurotoxic properties and may therefore play a role in the m olecular pathogenesis of Alzheimer's disease. We have identified solution c onditions under which two types of soluble oligomers of A beta 40 could be trapped and stabilized for an extended period of time. The first type of ol igomers comprises a mixture of dimers/tetramers which are stable at neutral PH and low micromolar concentration, for a period of at least four weeks. The second type of oligomer comprises a narrow distribution of particles th at are spherical when examined by electron microscopy and atomic force micr oscopy. The number average molecular mass of this distribution of particles is 0.94 MDa, and they are are stable at pH 3 for at least four weeks. Circ ular dichroism studies indicate that the dimers/tetramers possess irregular secondary structure that is not alpha-helix or beta-structure, while the 0 .94 MDa particles contain beta-structure. Fluorescence resonance energy tra nsfer experiments indicate that A beta 40 moieties in amyloid fibrils or pr otofibrils are more similar in structure to those in the 0.94 MDa particles than those in the dimers/tetramers. These findings indicate that soluble o ligomeric forms of A beta peptides can be trapped for extended periods of t ime, enabling their study by high resolution techniques that would not othe rwise be possible. (C) 2000 Academic Press.