High resolution scanning tunnelling microscopy of the β-amyloid protein (Aβ1-40) of Alzheimer's disease suggests a novel mechanism of oligomer assembly

The aggregation of the beta-amyloid protein (A beta) is an important step in the pathogenesis of Alzheimer's disease. There is increasing evidence that lower molecular weight oligomeric forms of A beta may be the most toxic species in vivo. However, little is known about the structure of A beta oligomers. In this study, scanning tunnelling microscopy (STM) was used to examine the structure of A beta monomers, dimers and oligomers. A beta 1-40 was visualised by STM on a surface of atomically flat gold. At low concentrations (0.5 mu M) small globular structures were observed. High resolution STM of these structures revealed them to be monomers of A beta. The monomers measured approximately 3-4 nm in diameter. Internal structure was seen in many of the monomers consistent with a conformation in which the polypeptide chain is folded into 3 or 4 domains. Oligomers were seen after ageing the A P solution for 24 h. The oligomers were also 3-4 nm in width and appeared to be formed by the end-to-end association of monomers with the polypeptide chain oriented at 90 degrees to the axis of the oligomer. The results suggest that the oligomer formation can proceed through a mechanism involving the linear association of monomers. (c) 2006 Elsevier Inc. All rights reserved.