We hypothesize that soluble amyloid beta-protein (Abeta) oligomers are key effectors of neurotoxicity and? may be a primary cause of Alzheimer's disease (AD). Consequently, inhibition of Abeta Oligomerization? is an attractive strategy for preventing and treating AD. We propose to use a systematic, rational? design approach for preparation and structure-activity studies of Abeta Oligomerization inhibitors. We? will focus our efforts on inhibitors of early Abeta(1-42) oligomers termed """"""""paranuclei."""""""" We choose early? Abeta(1-42) oligomers as our primary target because Abeta(1-42) is particularly linked to AD and because? inhibition of early assembly of Abeta(1-42) will alleviate the neurotoxic effects, both of the oligomers? themselves and of the larger neurotoxic assemblies, protofibrils and fibrils, for which paranuclei are? precursors. Our design in based on recent experimental and modeling data that delineate structural? features of paranucleus assembly, including primary-quaternary structure relationships and? conformation of the C-terminus of Abeta(1-42). This region is responsible directly for the enhanced? toxicity and distinct Oligomerization pattern of Abeta(1-42) relative to the more abundant alloform,? Abeta(1-40). The inhibitor design process is tightly integrated with the structural and biological projects? within the overall Program. The design process not only will benefit from the structural data? generated by the Program members, but also will feed back into structural studies and provide? further understanding of how particular regions and residues in Abeta interact with each other to form? oligomers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG027818-01
Application #
7112795
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8 (J2))
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2006-04-01
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$247,449
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hayden, Eric Y; Conovaloff, Joseph L; Mason, Ashley et al. (2017) Preparation of pure populations of covalently stabilized amyloid ?-protein oligomers of specific sizes. Anal Biochem 518:78-85
Zheng, Xueyun; Wu, Chun; Liu, Deyu et al. (2016) Mechanism of C-Terminal Fragments of Amyloid ?-Protein as A? Inhibitors: Do C-Terminal Interactions Play a Key Role in Their Inhibitory Activity? J Phys Chem B 120:1615-23
Yamin, Ghiam; Huynh, Tien-Phat Vuong; Teplow, David B (2015) Design and Characterization of Chemically Stabilized A?42 Oligomers. Biochemistry 54:5315-21
Williams, Thomas L; Urbanc, Brigita; Marshall, Karen E et al. (2015) Europium as an inhibitor of Amyloid-?(1-42) induced membrane permeation. FEBS Lett 589:3228-36
Hayden, Eric Y; Yamin, Ghiam; Beroukhim, Shiela et al. (2015) Inhibiting amyloid ?-protein assembly: Size-activity relationships among grape seed-derived polyphenols. J Neurochem 135:416-30
Barz, Bogdan; Urbanc, Brigita (2014) Minimal model of self-assembly: emergence of diversity and complexity. J Phys Chem B 118:3761-70
Toal, Siobhan; Meral, Derya; Verbaro, Daniel et al. (2013) pH-Independence of trialanine and the effects of termini blocking in short peptides: a combined vibrational, NMR, UVCD, and molecular dynamics study. J Phys Chem B 117:3689-706
Roychaudhuri, Robin; Yang, Mingfeng; Deshpande, Atul et al. (2013) C-terminal turn stability determines assembly differences between A?40 and A?42. J Mol Biol 425:292-308
Wu, Chun; Shea, Joan-Emma (2013) Structural similarities and differences between amyloidogenic and non-amyloidogenic islet amyloid polypeptide (IAPP) sequences and implications for the dual physiological and pathological activities of these peptides. PLoS Comput Biol 9:e1003211
Meral, Derya; Urbanc, Brigita (2013) Discrete molecular dynamics study of oligomer formation by N-terminally truncated amyloid ?-protein. J Mol Biol 425:2260-75

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