The starting point of this proposal is the observation that a disruption of neuronal polarity is an early aspect of the Alzheimer neuritic lesions. These lesions consist of tau-immunoreactive swollen neurites both around the senile plaques and free in the neuropil. There is remarkable agreement among investigators that these lesions, rather than amyloid deposition alone, correlate best with the presence of clinical dementia. A significant aspect of these neurites is the aberrant localization of tau protein, normally an axonal microtubule-associated protein, to the somatodendritic compartment. This displacement can be observed in """"""""neuropil threads"""""""" even before the more gross distortions of cell shape occur. Recently, using antisense techniques, we have discovered that tau may have a role in the generation of neuronal polarity. In this case loss of the correct compartmentation of tau may represent a fundamental disruption of neurite identity. The subject of this proposal is to learn basic information about how the tau protein can effect polarity decisions. The central hypothesis is that the regulation of the binding of tau to microtubules is a mediator of polarity and the phosphorylation state of tau, in a complex balance between kinase and phosphatase activity, regulates this binding. The sequence of experiments performed in neuronal culture will quantitate detergent extractable tau as a function of the acquisition of polarity, assess the phosphorylation state and turnover of free and bound tau, and directly probe for kinases and/or phosphatases that may mediate this partitioning.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029031-02
Application #
3415762
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1991-07-29
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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