Mimicry of Amyloid Oligomers Amyloid oligomers now thought to be the damaging molecular species in Alzheimer's disease, Parkinson's disease, and many other amyloid diseases. Understanding the structures of these oligomers is essential to understanding their mechanism of action, and quite possibly to developing drugs to prevent or treat these diseases. Studying the structures of the oligomers at high resolution is challenging, because the oligomers are heterogeneous and dynamic, forming a variety of sizes and structures that can interconvert. The oligomers are metastable, with fibrils being the more thermodynamically stable species. Only a few studies have provided glimpses of amyloid oligomers at atomic resolution. Thus far, the there are no atomic-resolution structures of oligomers of the beta-amyloid peptide, Abeta, the 40 or 42 amino acid polypeptide closely associated with Alzheimer's disease. This proposal aims to determine the structures of oligomers formed by Abeta by incorporating key fragments of Abeta into macrocyclic beta-sheet peptides designed to mimic the key beta-hairpin building blocks that are thought to make up Abeta oligomers. The PI has determined X-ray crystallographic structures at atomic resolution of trimers formed macrocyclic beta-sheet peptides containing fragments from the central and the C-terminal regions of Abeta. The trimers have a hitherto unprecedented structure consisting of a triangular arrangement of beta-hairpins that pack together at the three vertices. The trimers further assemble to form hexamers and dodecamers. This proposal aims to build on the discovery of these trimers and higher-order oligomeric assemblies. The broad overarching goal is to understand the relationship between the atomic-resolution structures of the oligomers and their biological and biophysical properties. To achieve these goals, the PI will synthesize macrocyclic beta-sheet peptides that incorporate different aspects of Abeta structure, determine the X-ray crystallographic structures of the oligomers that these peptides form, measure their cytotoxicity, elucidate their mechanisms of cytotoxcity, and correlate their cytotoxicity and their crystallographic structure by means of biophysical studies of their solution-phase properties.

Public Health Relevance

Mimicry of Amyloid Oligomers Oligomers of peptides and proteins are involved in many devastating neurodegenerative disorders, including Alzheimer's disease and the prion diseases. This proposal seeks to understand and control oligomer formation through the use of chemical model systems. The knowledge that is gained through these studies may eventually lead to new therapies for these diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Fabian, Miles
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University of California Irvine
Schools of Arts and Sciences
United States
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Salveson, Patrick J; Haerianardakani, Sepehr; Thuy-Boun, Alexander et al. (2018) Repurposing Triphenylmethane Dyes to Bind to Trimers Derived from A?. J Am Chem Soc 140:11745-11754
Kreutzer, Adam G; Nowick, James S (2018) Elucidating the Structures of Amyloid Oligomers with Macrocyclic ?-Hairpin Peptides: Insights into Alzheimer's Disease and Other Amyloid Diseases. Acc Chem Res 51:706-718
Yoo, Stan; Zhang, Sheng; Kreutzer, Adam G et al. (2018) An Efficient Method for the Expression and Purification of A?(M1-42). Biochemistry 57:3861-3866
Salveson, Patrick J; Haerianardakani, Sepehr; Thuy-Boun, Alexander et al. (2018) Controlling the Oligomerization State of A?-Derived Peptides with Light. J Am Chem Soc 140:5842-5852
Salveson, Patrick J; Spencer, Ryan K; Kreutzer, Adam G et al. (2017) X-ray Crystallographic Structure of a Compact Dodecamer from a Peptide Derived from A?16-36. Org Lett 19:3462-3465
Kreutzer, Adam G; Spencer, Ryan K; McKnelly, Kate J et al. (2017) A Hexamer of a Peptide Derived from A?16-36. Biochemistry 56:6061-6071
Kreutzer, Adam G; Yoo, Stan; Spencer, Ryan K et al. (2017) Stabilization, Assembly, and Toxicity of Trimers Derived from A?. J Am Chem Soc 139:966-975
Truex, Nicholas L; Nowick, James S (2017) Transmembrane Proteins: Amyloids Hidden in Plain Sight? Biochemistry 56:4735-4736
Kreutzer, Adam G; Hamza, Imane L; Spencer, Ryan K et al. (2016) X-ray Crystallographic Structures of a Trimer, Dodecamer, and Annular Pore Formed by an A?17-36 ?-Hairpin. J Am Chem Soc 138:4634-42
Truex, Nicholas L; Nowick, James S (2016) Coassembly of Peptides Derived from ?-Sheet Regions of ?-Amyloid. J Am Chem Soc 138:13891-13900

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