Alzheimer's disease (AD) and some other neurodegenerative diseases are characterized by a progressive accumulation of neurofibrillary tangles (NFT) and amyloid-rich senile plaques (SP). Although not restricted to AD, the number of SPs and NFTs correlates with the severity of dementia. The tangles are most probably formed from tau, a microtubule-associated protein, and other brain proteins, like neurofilaments (NFs). We identified a serine residue on human tau which, when phosphorylated, changes the normal protein to A68, a group of polypeptides that are AD- specific and present in NFTs. We also demonstrated that in certain circumstances, phosphorylation changes the conformation of synthetic peptides corresponding to human NF and tau from a helical-turn structure to beta-pleated sheets that are characteristic of the tangles at the electron microscopic level. Phosphorylation probably also plays a vital role in the function, transport, degradation, etc., of these and other neuronal cytoskeletal proteins. The phosphorylation sites of NF and tau are embedded in similar amino acid regions and have a high metal ion binding potential. We propose to synthesize non-phosphorylated and phosphorylated peptides corresponding to normal and abnormal phosphorylation sites of human tau protein. We will use circular dichroism (CD), nuclear magnetic resonance (NMR) and Fourier-transform infrared (FT-IR) spectroscopy to determine the conformation of the peptides in different solvents and environmental conditions. We are looking for phosphate acceptor sites that may serve as cores for intermolecular aggregate formation after abnormal post- translational modifications have changed the conformation. We also propose to extend these studies to those fragments of NF that abet the deposition of tau and thereby give rise to the known microscopic structure of NFTs. These studies will give insights into the topographical and environmental requirements for deposits of abnormal proteins in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG010670-04
Application #
2051903
Study Section
Special Emphasis Panel (SRC (33))
Project Start
1991-09-29
Project End
1996-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Otvos Jr, L; Feiner, L; Lang, E et al. (1994) Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404. J Neurosci Res 39:669-73
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Lang, E; Szendrei, G I; Lee, V M et al. (1994) Spectroscopic evidence that monoclonal antibodies recognize the dominant conformation of medium-sized synthetic peptides. J Immunol Methods 170:103-15
Gorbics, L; Urge, L; Otvos Jr, L (1994) Comparative and optimized dabsyl-amino acid analysis of synthetic phosphopeptides and glycopeptides. J Chromatogr A 676:169-76
Otvos Jr, L; Szendrei, G I; Lee, V M et al. (1993) Human and rodent Alzheimer beta-amyloid peptides acquire distinct conformations in membrane-mimicking solvents. Eur J Biochem 211:249-57
Szendrei, G I; Lee, V M; Otvos Jr, L (1993) Recognition of the minimal epitope of monoclonal antibody Tau-1 depends upon the presence of a phosphate group but not its location. J Neurosci Res 34:243-9

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