Alzheimer's disease (AD), the most common cause of dementia in middle and late life, is characterized by progressive impairments in memory, language, visuospatial perceptions, and behavior. Clinical criteria have been defined for possible and probable AD, but a diagnosis of AD requires the histological demonstration of neurofibrillary tangles and senile plaques. The major constituent of neurofibrillary tangles, neuropil threads, and neurites, is paired helical filaments (PHF), which contain modified tau proteins. Normally, alternative splicing of messenger ribonucleic acid (mRNA) transcribed from a single gene gives rise to variations in tau isoform expression. In the present proposal, variations in tau isoform expression will be examined in two models of neuronal injury (i.e., axonal transection with and without subsequent regeneration, and aluminum-induced neurofibrillary abnormalities), using a combination of in situ hybridization, RNA blotting, and quantitative polymerase chain reaction procedures. The roles that tau isoform expression play in these animal models will lend insight into the functions of various isoforms. Furthermore, the examination of alterations of tau isoform expression that involve-simple models of neuronal injury will lay the foundation for the study of tau in more complex models and, eventually, for studies of this class of protein in aging and neurodegenerative diseases, including AD. The overexpression of mRNA-encoding tau or any of the tau isoforms could contribute to the formation of PHF seen in AD. Structural and functional modulation of proteins is frequently regulated via alternative splicing, therefore, differential involvement of tau isoforms in PHF is quite likely. Studies such as these, which elucidate factors that lead to the formation of abnormal structures in AD, should be useful in the development of new treatment strategies for the cytoskeletal abnormalities that occur in individuals with AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS030460-02
Application #
3417351
Study Section
Neurology A Study Section (NEUA)
Project Start
1992-09-26
Project End
1995-08-31
Budget Start
1992-09-26
Budget End
1993-08-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153