S100B MODULATES BETA-AMYLOID-INDUCED NEUROTOXICITY

Our results suggest that S100B behaves as a neurotrophic factor counteracting beta-amyloid-induced neurotoxicity. Such an effect seems to be dependent on RAGE binding, stimulation of ERK1/2, activation of NF-kB and up-regulation of bcl-2 expression. Recent data by Kogel et al. (2004) demonstrated an S100B-mediated cytoprotection of cultured rat hippocampal neurons subjected to a Ca2+-overloading following a glutamate receptor overactivation. Such a protective action was shown to depend on RAGE-mediated stimulation of the NF-kB pathway, which has been already related to prosurvival effects of treatments with nanomolar amounts of S100B in experimental models in vitro (Huttunen, 2000). Therefore our data confirm the neuroprotective role of S100B added at nanomolar concentration, exerted through binding to RAGE and the subsequent translocation of NF-kB and activation of target genes implicated in cell survival. In this connection it is interesting to notice that activated astrocytes overexpressing S100B were detected in the surroundings of neuritic beta-amyloid plaques of Alzheimer¡¦s disease (AD) (Mrak et al., 1996) and elevated levels of S100B were observed in cerebrospinal fluid of AD patients compare to age-matched controls. Our data suggest that S100B play a neuroprotective role at the beginning of the neurodegenerative process, characterizing the development of AD. On the contrary, when extracellular levels of S100B increase, reaching ƒÝM concentration, its role shifts to neurotoxicity, probably stimulating the activation of the NF-kB target gene inducible nitric oxide synthase (Hu et al., 1996) or enhancing RAGE expression on cell membranes, giving rise to an increased number of available ƒÒamyloid binding sites, since RAGE is one of known beta-amyloid receptors. In fact it was shown that beta-amyloid-RAGE interaction induces a cascade of events leading to the generation of reactive oxygen species in microglial cells (Mruthinti S. et al., 2003).