The applicants have discovered an entirely new and powerful method of polymerizing tau protein into filaments resembling the straight filaments found in the neurofibrillary pathology of Alzheimer's disease. The inducing agents are membrane phospholipids and fatty acids that are known to function as signal transduction molecules in vivo. The resultant filaments are regular, and available in large quantities. By analyzing the structure and genesis of these filaments, they will address important questions regarding tau filament formation and neurodegenerative disease. Which membrane-associated components are capable of stimulating tau self-association and polymerization? Does the resultant structure-activity-relationship point toward the involvement of known signal transduction mechanisms in filament biogenesis? What is the role of phosphorylation on tau self-assembly and intracellular stability? Four Aims are proposed to address these questions. 1) The process of tau filament formation will be quantified. Using a novel assembly assay, they will quantify the rate, extent, and ligand dependence of tau filament formation in vitro. 2) The structural features on tau required for filament formation will be determined. These studies will clarify the structural requirements of tau polymerization and the location of a ligand-binding site potentially useful for development of high-affinity agents for therapeutic and diagnostic applications. 3) The influence of post-translational modification on tau polymerization kinetics will be assessed. These studies will clarify the impact of phosphorylation and glycation on tau filament formation. 4) The effects of polymerization on tau structure will be determined. Using a combination of circular dichroism spectropolarimetry and hydrodynamic measurements, it will be determined whether tau adopts a defined structure upon filament formation. The results will have important implications for the feasibility of developing therapeutic agents capable of preventing, and premortem diagnostic agents capable of detecting, the formation of fibrillar pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG014452-01
Application #
2002359
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Oliver, Eugene J
Project Start
1997-04-15
Project End
2002-03-31
Budget Start
1997-04-15
Budget End
1998-03-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Huseby, Carol J; Kuret, Jeff (2016) Analyzing Tau Aggregation with Electron Microscopy. Methods Mol Biol 1345:101-12
Cisek, Katryna; Cooper, Grace L; Huseby, Carol J et al. (2014) Structure and mechanism of action of tau aggregation inhibitors. Curr Alzheimer Res 11:918-27
Schafer, Kelsey N; Cisek, Katryna; Huseby, Carol J et al. (2013) Structural determinants of Tau aggregation inhibitor potency. J Biol Chem 288:32599-611
Zhong, Qi; Congdon, Erin E; Nagaraja, Haikady N et al. (2012) Tau isoform composition influences rate and extent of filament formation. J Biol Chem 287:20711-9
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Cisek, Katryna; Kuret, Jeff (2012) QSAR studies for prediction of cross-? sheet aggregate binding affinity and selectivity. Bioorg Med Chem 20:1434-41
Thomas, Stefani N; Funk, Kristen E; Wan, Yunhu et al. (2012) Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach. Acta Neuropathol 123:105-17
Schafer, Kelsey N; Murale, Dhiraj P; Kim, Kibong et al. (2011) Structure-activity relationship of cyclic thiacarbocyanine tau aggregation inhibitors. Bioorg Med Chem Lett 21:3273-6
Funk, K E; Mrak, R E; Kuret, J (2011) Granulovacuolar degeneration (GVD) bodies of Alzheimer's disease (AD) resemble late-stage autophagic organelles. Neuropathol Appl Neurobiol 37:295-306
Chang, Edward; Kim, Sohee; Schafer, Kelsey N et al. (2011) Pseudophosphorylation of tau protein directly modulates its aggregation kinetics. Biochim Biophys Acta 1814:388-95

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