EPR studies of the structures of Abeta oligomers

Project Summary

Recent studies suggest that amyloid beta oligomers are the primary toxic species in the development of Alzheimer's disease. Different amyloid beta oligomers have been identified by different investigators. Because the molecular structures of these oligomers are unknown, it is impossible to know how many unique structures exist in the oligomers and how one type of oligomer differs from another type of oligomer. In this project, we will study the structures of two amyloid beta oligomers with a technique called electron paramagnetic resonance (EPR) spectroscopy. This work will help understand the structural basis of toxicity of amyloid beta oligomers and guide the development of new therapeutic strategies. Our experimental approach involves introducing a probe called spin label into the sequence of amyloid beta. Spin label gives rise to an “EPR spectrum”, from which structural information can be extracted. The distance between two spin labels can also be measured. These distances will serve as constraints for computation of structural models of these oligomers. EPR is a powerful technique for protein structure studies, but its application in Alzheimer's disease has been limited. We plan to explore the applications of existing EPR methods and develop new strategies to study these amyloid beta oligomers. Success in this project will pave the way for more extensive studies of not only Alzheimer's disease, but also other similar neurodegenerative diseases.