S-100B--NEURONAL GLIAL LINK TO ALZHEIMERS DISEASE

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The Program Project consists of the cohesive efforts of established scientists from separate institutions. The CORES and projects are integrated to test the hypothesis that S-100beta is linked to the neuropathology associated with Alzheimer's Disease (AD), as well as to further our understanding of neuronal/glial interactions in the control and operation of CNS growth factors. An administrative core and five research cores are proposed to facilitate the interactions necessary to cost- effectively utilize the individuals' expertise and the excellent support facilities available at the respective research centers. Five research projects will address three overall research areas using tissue culture. Research Area 1 will be to study the detailed actions of factors acting on astrocytes to regulate the synthesis and release of S-100beta (eg. IL-1, 5- HT, Ca++, and glucocorticoids). The results of this research area will provide clues to the identity of key astrocytic regulatory-substances that may be altered in AD, and which can be analyzed in our extensive collection of Alzheimer's brains. Research Area 2 will examine the molecular and cellular events in astrocytes resulting from exposure to s-100beta. Changes in signal transduction pathways and in astrocytic morphology and proliferation will be studied. Research Area 3 will explore the mechanism of action of S-100beta on neurite extension. Does S-100beta enter the neurons to interact with specific microtubule-associated-proteins and/or does it bind to a cell surface receptor and produce a response via specific second messenger systems? The Results obtained from these three research areas can then be translated into in vivo experiments using whole animals. Procedures such as cell transplantation, in situ hybridization and immunocytochemistry can be applied to specific brain regions in the adult or aged animal. Predictions arising from these studies will be tested on human post mortem tissue which includes a large collection of AD brains. Our multidisciplinary efforts are not concerned solely with understanding astroglial/neuronal interactions but strives to answer basic questions of the role of S-100beta in Alzheimer's disease.