Single-molecule imaging of amyloid-beta protein (Abeta) of Alzheimer's disease: from single-molecule structures to aggregation mechanisms and membrane interactions

Recent advances in single-molecule imaging have allowed unprecedented insight into the structure of biomolecules and, consequently, into the role the structure plays in biochemical processes. A particular process of interest is the aggregation of the amyloidβ protein (Aβ ), which is thought to be an important step in the pathogenesis of Alzheimer's disease: there is increasing evidence that Aβ oligomers may be the neurotoxic species in vivo. However, little is known about the structural organization of small Aβ oligomers. While an increasing number of studies report the atomic-level modeling of Aβ aggregation, there is still significant controversy over the specific architecture of Aβ oligomers and fibrils. The use of scanning probe microscopy techniques, including scanning tunneling microscopy (STM) and atomic force microscopy (AFM), may be able to bridge this gap in knowledge. Complementary microscopy techniques can reveal internal structure in many Aβ monomers, consistent with a conformation in which the polypeptide chain is folded into 2, 3 or 4 domains. In this chapter, we review the most recent studies on the high-resolution imaging of Aβ, and we re-examine different models of Aβ aggregation, fibril formation and membrane interactions.