High-resolution probing of early events in amyloid-β aggregation related to Alzheimer's disease

In Alzheimer's disease (AD), soluble oligomers of amyloid-beta (A beta) are emerging as a crucial entity in driving disease progression as compared to insoluble amyloid deposits. The lacuna in establishing the structure to function relationship for A beta oligomers prevents the development of an effective treatment for AD. While the transient and heterogeneous properties of A beta oligomers impose many challenges for structural investigation, an effective use of a combination of NMR techniques has successfully identified and characterized them at atomic-resolution. Here, we review the successful utilization of solution and solid-state NMR techniques to probe the aggregation and structures of small and large oligomers of A beta. Biophysical studies utilizing the commonly used solution and F-19 based NMR experiments to identify the formation of small size early intermediates and to obtain their structures, and dock-lock mechanism of fiber growth at atomic-resolution are discussed. In addition, the use of proton-detected magic angle spinning (MAS) solid-state NMR experiments to obtain high-resolution insights into the aggregation pathways and structures of large oligomers and other aggregates is also presented. We expect these NMR based studies to be valuable for real-time monitoring of the depletion of monomers and the formation of toxic oligomers and high-order aggregates under a variety of conditions, and to solve the high-resolution structures of small and large size oligomers for most amyloid proteins, and therefore to develop inhibitors and drugs.