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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
New York
United States
Zip Code
Mrak, Robert E; Griffin, W Sue T (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26:349-54
Sheng, J G; Mrak, R E; Jones, R A et al. (2001) Neuronal DNA damage correlates with overexpression of interleukin-1beta converting enzyme in APPV717F mice. Neurobiol Aging 22:895-902
Nicoll, J A; Mrak, R E; Graham, D I et al. (2000) Association of interleukin-1 gene polymorphisms with Alzheimer's disease. Ann Neurol 47:365-8
Russo, G L; van den Bos , C; Sutton, A et al. (2000) Phosphorylation of Cdc28 and regulation of cell size by the protein kinase CKII in Saccharomyces cerevisiae. Biochem J 351:143-50
Sheng, J G; Zhu, S G; Jones, R A et al. (2000) Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo. Exp Neurol 163:388-91
Griffin, W S; Nicoll, J A; Grimaldi, L M et al. (2000) The pervasiveness of interleukin-1 in alzheimer pathogenesis: a role for specific polymorphisms in disease risk. Exp Gerontol 35:481-7
Zhu, S G; Sheng, J G; Jones, R A et al. (1999) Increased interleukin-1beta converting enzyme expression and activity in Alzheimer disease. J Neuropathol Exp Neurol 58:582-7
Karson, C N; Mrak, R E; Schluterman, K O et al. (1999) Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for 'hypofrontality'. Mol Psychiatry 4:39-45
Nishi, M; Azmitia, E C (1999) Agonist- and antagonist-induced plasticity of rat 5-HT1A receptor in hippocampal cell culture. Synapse 31:186-95
Royston, M C; McKenzie, J E; Gentleman, S M et al. (1999) Overexpression of s100beta in Down's syndrome: correlation with patient age and with beta-amyloid deposition. Neuropathol Appl Neurobiol 25:387-93

Showing the most recent 10 out of 59 publications