We hypothesize that altered protein phosphorylation reactions are deleterious to neurons and might be involved in neurodegeneration in Alzheimer's disease (AD). It is now well recognized that protein phosphorylation is a key biochemical reaction required for the regulation of cell growth and cell survival. Thus, it is possible that aberrant phosphorylation reactions play an important role in the neuronal degeneration. There are age-associated declines of some protein kinases. Therefore, it is possible that the neurodegeneration observed in AD which is an age-associated disease, might be at least partly explained by the altered protein phosphorylation reactions. In affected neurons, there are neurofibrially tangles composed of cytoskeletal proteins, ubiquitin, and still unknown molecules. Immunohistochemical studies have revealed that the constituents of tangles as well as proteins in neurons at risk are excessively phosphorylated. Our in vitro phosphorylation study has supported the notion that the phosphorylation cascade reactions are aberrant in AD. We have identified protein kinase C (PKC), casein kinase II (CK-ll), and protein tyrosine kinase (PTK) as altered in AD. Interestingly, PKC alteration might be associated with neuritic plaque pathology in AD and CK-ll alteration with neurofibrillary tangle pathology. In the current proposal, we extend this study to their substrate proteins employing biochemical and immunohistochemical techniques. Furthermore, we attempt to identify an unknown protein kinase, the activity of which, measured with exogenous histone lll-S, is increased in AD, and a phosphoprotein, P60, which was found by in vitro phosphorylation of AD cytosol. In addition, possible phosphorylation of t, a tangle constituent, by CK-ll and other kinases will be studied. The purpose of the project is to pull all the altered molecules of protein phosphorylation into a cohesive cascade of AD pathology. To this end, we will study the localization of various components of protein phosphorylation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG008205-05
Application #
3119712
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1988-08-01
Project End
1996-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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