Mechanisms of neurotoxicity in Alzheimer's disease

Zhefeng Guo, PhD
University of California, Los Angeles (Los Angeles, CA)
Year Awarded:
2010
Grant Duration:
April 1, 2010 to June 30, 2012
Disease:
Alzheimer's Disease
Award Amount:
$150,000
Grant Reference ID:
A2010362
Award Type:
Pilot
Award Region:
US Southwestern
Zhefeng Guo, PhD

EPR studies of the structures of Abeta oligomers

Summary

Recent studies suggest that amyloid beta oligomers, or aggregation of only a few amyloid beta molecules, are the primary toxic species in the development of Alzheimer's disease. In this project, we will study the structures of two amyloid beta oligomers with electron paramagnetic resonance (EPR) spectroscopy. This work will help understand the structural basis of neurotoxicity of amyloid beta oligomers and guide the development of new therapeutic strategies.

Details

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.

Publications

Ngo, S., and Guo, Z. (2011). Key residues for the oligomerization of A?42 protein in Alzheimer's disease. Biochem Biophys Res Commun 414, 512-516. PubMed Icon Google Scholar Icon

Agopian, A., and Guo, Z. (2012). Structural origin of polymorphism for Alzheimer's amyloid-? fibrils. Biochem J 447, 43-50. PubMed Icon Google Scholar Icon

Ngo, S., Chiang, V., and Guo, Z. (2012). Quantitative analysis of spin exchange interactions to identify ? strand and turn regions in Ure2 prion domain fibrils with site-directed spin labeling. J Struct Biol, doi: 10.1016/j.jsb.2012.1008.1008.

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