beta-Amyloid regulates gene expression of glial trophic substance S100 beta in C6 glioma and primary astrocyte cultures.
S100 beta, 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 S100 beta protein, and astrocytes surrounding neuritic plaques exhibit highly elevated levels of S100 beta immunostaining. A major constituent of plaques, beta-amyloid, has been reported to have neurotoxic and neurotrophic effects in vitro. In our study we examined the responses of CNS glia to beta-amyloid. C6 glioma cells and primary rat astrocyte cultures were treated with beta A(1-40) peptide at doses up to 1 microM. Weak mitogenic activity, measured by [3H]thymidine incorporation, was observed. Northern blot analysis revealed increases of S100 beta mRNA within 24 h in a dose-dependent manner. Nuclear run-off transcription assays showed that beta A(1-40) specifically induced new synthesis of S100 beta mRNA in cells maintained in serum, but under serum-free conditions, there was a general elevation of several mRNA species. Corresponding increases of S100 beta protein synthesis were observed by immunoprecipitation of 35S-labeled cellular proteins. To evaluate whether this effect of beta-amyloid was mediated via neurokinin receptors or by calcium fluxes, various agonists and antagonists were tested and found to be ineffective at stimulating S100 beta synthesis. In sum, these in vitro data suggest that in neuropathological conditions, beta-amyloid itself is an agent which may provoke chronic gliosis and the production of trophic substances by astrocytes.
Peña
L A
LA
Keck Structural Biology Laboratory, Beckman Neuroscience Center, Cold Spring Harbor, NY 117240-2220, USA.
Brecher
C W
CW
Marshak
D R
DR
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002478:Cells, Cultured; D004314:Down Syndrome / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009414:Nerve Growth Factors / Q000235:genetics*; D009457:Neuroglia / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D002135:Calcium-Binding Proteins; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human