S100beta is a calcium binding protein produced and released by astroglial cells in the CNS. The gene for human S100beta maps to the Down syndrome region of chromosome 21, and Alzheimer's disease. As a disulfide-linked dimer, S100beta has neurotrophic activity on certain neuronal populations and mitogenic activity on astroglia. Thus, S100beta may help coordinate development and maintenance of the CNS by stimulating both the differentiation of neurons and the proliferation of glia. Furthermore, the expression could have profound detrimental effects on nervous system function and perhaps contribute to the neuropathologies observed in age- related disorders like Alzheimer's disease. However, no direct data are available concerning the relationship between altered S100beta levels or activity and the neuropathological manifestations of age-related disorders. It is the goal of this proposal to fill a void in our knowledge of the molecular mechanisms of S100beta, through its ability to affect glial cell morphology and proliferation, contributes to the gliosis in Alzheimer's disease.
The specific aims are: 1) to elucidate the generality and extent of S100beta activity as a growth factor by testing S100beta effects on rat primary astrocytes from different brain regions and of different maturational states; 2) to examine the structural requirements for S100beta activity by utilizing site-directed mutagenesis of an S100beta gene; and 3) to examine the mechanistic coupling of S100beta the glial cell. These studies will provide the necessary knowledge to pursue longer-term studies aimed at probing molecular mechanisms at a more detailed level. In addition, the structure-function correlates defined in these studies may allow the eventual design of selective agonists or antagonists based on the S100beta structure or mechanism of action, and thus provide the potential for future development of pharmacological reagents useful for maintenance or repair of neuronal and glial function. Finally, this research project, combined with the results from the other members of this program will provide the basic database of mechanistic information required to address how abnormal regulation of S100beta activity may be linked to the neuropathologies observed in Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010208-03
Application #
3746172
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
New York University
Department
Type
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
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