S100B promotes development and maturation in the mammalian brain. However, prolonged or extensive exposure can lead to neurodegeneration. Two important functions of S100B in this regard, are its role in the development and plasticity of the serotonergic neurotransmitter system, and its role in the cascade of glial changes associated with neuroinflammation. Both of these processes are therefore accelerated towards degeneration in disease processes wherein S100B is increased, notably, Alzheimer's disease (AD) and Down syndrome (DS). In order to study the role of S100B in this context, we have examined S100B overexpressing transgenic mice. Similar to AD and DS, the transgenic animals show a profound change in serotonin innervation. By 28 weeks of age, there is a significant loss of terminals in the hippocampus. Similarly, the transgenic animals show neuroinflammatory changes analogous with AD and DS. These include decreased numbers of mature, stable astroglial cells, increased numbers of activated microglial cells and increased microglial expression of the cell surface receptor RAGE. Eventually, the S100B transgenic animals show neurodegeneration and the appearance of hyperphosphorylated tau structures, as seen in late stage DS and AD. The role of S100B in these conditions is discussed.

S100B is a calcium-binding protein released by astroglial cells of the brain capable of producing numerous extracellular effects. Although the direct molecular mechanism remains unknown, these effects can be trophic including differentiation, growth, recovery, and survival of neurons when the S100B protein is mainly oxidized and neurotoxic including apoptosis and neuroinflammatory processes marked by microglial activation when in a reduced state. S100B and its receptor RAGE (receptor for advanced glycation end products) have been found to be increased in Alzheimer's disease, Down syndrome, with tissue trauma and ischemia. In the current study, we examined the binding of the S100B receptor (RAGE) on microglial cells and the developmental effects of the antioxidant vitamin E on microglial activation and the upregulation of RAGE in an S100B over-expressing mouse model of pathological aging. We report that RAGE is co-localized on activated microglial cells and vitamin E induced dramatic increases in microglial activation as well as total microglial relative optical density that was accompanied by upregulation of the RAGE receptor, particularly in the CA1 region of the hippocampus. Our findings suggest further investigation into the potential role of vitamin E in reducing the oxidation state of the S100B protein and its influence on neuroinflammatory processes marked by microglial activation in vivo.