β-Amyloid regulates gene expression of glial trophic substance S100β in C6 glioma and primary astrocyte cultures

S100β, a calcium-binding protein synthesized by CNS astrocytes, has trophic effects in vitro (neurite extension and glial proliferation). In Alzheimer's disease and Down's syndrome, severely afflicted brain regions exhibit up to 20-fold higher levels of S100β protein, and astrocytes surrounding neuritic plaques exhibit highly elevated levels of S100β immunostaining. A major constituent of plaques, β-amyloid, has been reported to have neurotoxic and neurotrophic effects in vitro. In our study we examined the responses of CNS glia to β-amyloid. C6 glioma cells and primary rat astrocyte cultures were treated with βA(1-40) peptide at doses up to 1 μM. Weak mitogenic activity, measured by [³H]thymidine incorporation, was observed. Northern blot analysis revealed increases of S100β mRNA within 24 h in a dose-dependent manner. Nuclear run-off transcription assays showed that βA(1-40) specifically induced new synthesis of S100β mRNA in cells maintained in serum, but under serum-freconditions, there was a general elevation of several mRNA species. Corresponding increases of S100β protein synthesis were observed by immunoprecipitation of ³⁵S-labeled cellular proteins. To evaluate whether this effect of β-amyloid was mediated via neurokinin receptors or by calcium fluxes, various agonists and antagonists were tested and found to be ineffective at stimulating S100β synthesis. In sum, these in vitro data suggest that in neuropathological conditions, β-amyloid itself is an agent which may provoke chronic gliosis and the production of trophic substances by astrocytes.