P4–030: Scanning tunnelling microscopy of the β–amyloid protein (Aβ) of Alzheimer's disease suggests a model of oligomer assembly

The aggregation of the β–amyloid protein (Aβ) is an important step in the pathogenesis of Alzheimer's disease. Although Aβ can form high molecular weight amyloid fibrils in solution, there is increasing evidence that protofibrils and even lower molecular weight oligomeric forms of Aβ may be the most toxic species in vivo. Little is known about how Aβ oligomers are formed from monomeric Aβ and thus it is important to gain a better understanding of the mechanism of assembly. In this study, scanning tunnelling microscopy (STM) was used to examine the structure of Aβ monomers, dimers and oligomers. Aβ1–40 was visualized by STM on a surface of atomically flat gold. At low concentrations (0.5 μM) which favor monomeric Aβ, small globular structures were observed. High resolution STM of these structures showed them to be monomers and dimers of Aβ. The monomers were round and measured approximately 3 nm in diameter. Internal structure was consistent with a conformation in which the polypeptide chain is folded into 3 or 4 anti–parallel domains. Oligomers were seen after aging the Aβ solution for 24 hr. The oligomers appeared to be formed by the end–to–end association of monomers with the polypeptide chain oriented at 90° to the axis of the oligomer. The results suggest that the oligomer formation follows a linear aggregation mechanism in which each monomer is folded into an anti–parallel β–sheet structure, resulting in a cross–β configuration.