Supplement for 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. 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. Grant GM097562 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. Grant GM097562 aims to build on the discovery of these trimers and the higher-order oligomeric assemblies that they form. 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 cytotoxicity, and correlate their cytotoxicity and their crystallographic structure by means of biophysical studies of their solution-phase properties. In the course of these studies, an unanticipated opportunity to accelerate our research has emerged. We have discovered that we can generate polyclonal antibodies against our amyloid oligomer mimics and that these antibodies react with molecular entities in the brain tissue of Alzheimer's disease transgenic mice and humans. We believe that these molecular entities are amyloid oligomers formed by Abeta in the brain. This finding is important, because it allows us to more deeply study the biological properties of our amyloid oligomer mimics and better establish their biological relevance. We visualize the interaction of the antibodies with brain tissue by fluorescence microscopy. These studies are limited by access to the high-end confocal microscopes in the Optical Biology Core Facility, which is located in a different building and are heavily booked, thus delaying research. An all-in-one fluorescence microscope will accelerate the research by allowing the rapid imaging of samples on a day-to-day basis, without delays.

Public Health Relevance

Supplemental support is requested for the purchase of an all-in-one fluorescence microscope that will enhance our NIH funded research on amyloid oligomer formation. Our success to date means that we can accelerate efforts to elucidate the biological properties of amyloid oligomers, where the lack of the requested instrument is a rate limiting step, thus enhancing understanding of the molecular processes in Alzheimer's disease. This application is coordinated with those of another NIGMS funded scientist.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM097562-07S1
Application #
9707408
Study Section
Program Officer
Fabian, Miles
Project Start
2012-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Truex, Nicholas L; Nowick, James S (2017) Transmembrane Proteins: Amyloids Hidden in Plain Sight? Biochemistry 56:4735-4736
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
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; Wang, Yilin; Nowick, James S (2016) Assembly of Peptides Derived from ?-Sheet Regions of ?-Amyloid. J Am Chem Soc 138:13882-13890
Truex, Nicholas L; Nowick, James S (2016) Coassembly of Peptides Derived from ?-Sheet Regions of ?-Amyloid. J Am Chem Soc 138:13891-13900
Spencer, Ryan K; Kreutzer, Adam G; Salveson, Patrick J et al. (2015) X-ray Crystallographic Structures of Oligomers of Peptides Derived from ?2-Microglobulin. J Am Chem Soc 137:6304-11
Spencer, Ryan K; Nowick, James S (2015) A Newcomer's Guide to Peptide Crystallography. Isr J Chem 55:698-710
Pham, Johnny D; Spencer, Ryan K; Chen, Kevin H et al. (2014) A fibril-like assembly of oligomers of a peptide derived from ?-amyloid. J Am Chem Soc 136:12682-90

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