The neuropathological hallmarks of Alzheimer's disease (AD) are the abundance of intraneuronal neurofibrillary tangles and the extracellular deposition of the Abeta peptide as amyloid plaques. Extensive genetic and cell viability studies support a key role for the Abeta peptide in AD neurodegeneration. The Abeta pathologic effects are related to the formation of insoluble aggregates dominated by beta-sheet structures. Biochemical studies suggest that the longer, 42-residue Abeta (1-42) is more pathogenic than the shorter, 40-residue Abeta (1-40), due to its greater in vitro tendency to aggregate and precipitate as amyloid. Nonetheless, a molecular basis for the greater pathogenicity of the Abeta (1-42) has yet to be determined. Our laboratory is one of the few research groups that has successfully applied high-resolution NMR methods to study the structure and aggregational properties of the Abeta peptides. The NMR approach is extremely powerful for studying proteins, in that it can detect site-specific aspects of the structures and dynamics in solution at the atomic level. Using NMR, we have discovered differences between the monomeric forms of the Abeta (1-40) and Abeta (1-42) in water solution at pH 7.2, in which the Abeta (1-42) displayed multiple NH peaks for Val36, Gly37, Gly38, and Val39, a region previously implicated to contain a cis peptide bond that could be important for initiating beta-amyloidosis. Our NMR results may account for the greater beta-aggregation of the Abeta (1-42), and we hypothesize that the monomeric Abeta (1-42) adopts a unique structure not present for monomeric Abeta (1-40). This application contains three well-coupled, specific aims.
The first aim will be to explore the effects of D-Asp, D-Ser and iso-Asp on the structure and beta-aggregation rates of the Abeta (1-42). We hypothesize that these permutations alter the structure in a manner to create a seed"""""""" that nucleates beta-amyloidosis.
Aim 2 will examine the dynamics of the Abeta association in aqueous solution using 15N and 13C NMR relaxation studies. We will carefully compare the site-specific association of the Abeta (1-40) and Abeta (1-42), and determine if cis-trans isomerization occurs at the Gly37-Gly38 peptide bond for monomeric Abeta (1-42). To locate putative inhibitor bindings sites or surfaces, Aim 3 will conduct NMR binding studies with macromolecules (such as ApoE and ApoJ) and presumed amyloid inhibitors with monomeric Abeta (1-40) and Abeta (1-42). This information has potential for additives and drug candidates to interfere with the beta-aggregation process and provide detailed structural information about the biding mode of amyloid inhibitors. With these data, a more rational approach to the design of less toxic and more effective inhibitors of beta-amyloidosis will be explored by collaboration with scientists in the medical school.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014363-08
Application #
6721262
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Snyder, Stephen D
Project Start
1997-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2006-03-31
Support Year
8
Fiscal Year
2004
Total Cost
$223,473
Indirect Cost
Name
Case Western Reserve University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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