Alzheimer's disease is characterized by three major pathologic signs: neurofibrillary tangles within neurons, the amyloid that surrounds and invades cerebral blood vessels and the amyloid-rich plaques that replace degenerating nerve terminals. It is proposed to study the mechanism which causes the formation of these three debilitating phenomena. The known sequences of cytoskeletal proteins will be compared by established homology alignment algorithms and secondary predictive methods to search for commonality and relatedness. Special emphasis will be given to sequences containing suggested phosphorylation sites and those which are rich in glutamate and aspartate. Fragments (5-30 residues, phosphorylated and nonphorylated) of neurofilament (NF) and microtubule associated proteins (tau and MAP2) will be synthesized by using solid phase and classical synthetic methods. Their metal ion (Ca2+, Al3+, Mg2+, Na+ and K+) binding potential and concomitant conformational changes of these fragments, which may play a role in the formation of the pathologies mentioned above, will be explored by physical chemical procedures such as circular dichroism (CD) spectroscopy and CD titration. Molecular mechanics calculations, FTIR spectroscopy and, in selected cases, high resolution NMR studies will be pursued to complement CD studies. Enzymatic phosphorylation and dephosphorylation, as well as immunological studies, will be performed on selected peptides to test the widespread hypothesis that aberrant phosphorylation and hyperphosphorylation play a crucial role in the biochemistry of neurodegenerative diseases. Efforts will be made to find selective chelators for Al3+ ions to prevent the binding of the neurotoxic Al3+ to cytoskeletal proteins and delay the progress of Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG010002-01
Application #
3121955
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1991-09-30
Project End
1994-08-31
Budget Start
1991-09-30
Budget End
1992-08-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Brandeis University
Department
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454