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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097562-06
Application #
9205515
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
2011-04-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
6
Fiscal Year
2017
Total Cost
$262,263
Indirect Cost
$75,089
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; Wang, Yilin; Nowick, James S (2016) Assembly of Peptides Derived from β-Sheet Regions of β-Amyloid. J Am Chem Soc 138:13882-13890
Truex, Nicholas L; Nowick, James S (2016) Coassembly of Peptides Derived from β-Sheet Regions of β-Amyloid. J Am Chem Soc 138:13891-13900
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 Aβ17-36 β-Hairpin. J Am Chem Soc 138:4634-42
Spencer, Ryan K; Kreutzer, Adam G; Salveson, Patrick J et al. (2015) X-ray Crystallographic Structures of Oligomers of Peptides Derived from β2-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; Demeler, Borries; Nowick, James S (2014) Polymorphism of oligomers of a peptide from β-amyloid. J Am Chem Soc 136:5432-42
Pham, Johnny D; Spencer, Ryan K; Chen, Kevin H et al. (2014) A fibril-like assembly of oligomers of a peptide derived from β-amyloid. J Am Chem Soc 136:12682-90
Spencer, Ryan K; Li, Hao; Nowick, James S (2014) X-ray crystallographic structures of trimers and higher-order oligomeric assemblies of a peptide derived from Aβ(17-36). J Am Chem Soc 136:5595-8
Pham, Johnny D; Chim, Nicholas; Goulding, Celia W et al. (2013) Structures of oligomers of a peptide from β-amyloid. J Am Chem Soc 135:12460-7
Cheng, Pin-Nan; Pham, Johnny D; Nowick, James S (2013) The supramolecular chemistry of β-sheets. J Am Chem Soc 135:5477-92

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