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1.
J Biol Chem ; 277(36): 32985-91, 2002 Sep 06.
Article in English | MEDLINE | ID: mdl-12095987

ABSTRACT

We hypothesize that in neurodegenerative disorders such as Alzheimer's disease and human immunodeficiency virus encephalitis the neuroprotective activity of fibroblast growth factor 1 (FGF1) against several neurotoxic agents might involve regulation of glycogen synthase kinase-3beta (GSK3beta), a pathway important in determining cell fate. In primary rat neuronal and HT22 cells, FGF1 promoted a time-dependent inactivation of GSK3beta by phosphorylation at serine 9. Blocking FGF1 receptors with heparinase reduced this effect. The effects of FGF1 on GSK3beta were dependent on phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) because inhibitors of this pathway or infection with dominant negative Akt adenovirus blocked inactivation. Furthermore, treatment of neuronal cells with FGF1 resulted in ERK-independent Akt phosphorylation and beta-catenin translocation into the nucleus. On the other hand, infection with wild-type GSK3beta recombinant adenovirus-associated virus increased activity of GSK3beta and cell death, both of which were reduced by FGF1 treatment. Moreover, FGF1 protection against glutamate toxicity was dependent on GSK3beta inactivation by the PI3K-Akt but was independent of ERK. Taken together these results suggest that neuroprotective effects of FGF1 might involve inactivation of GSK3beta by a pathway involving activation of the PI3K-Akt cascades.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Fibroblast Growth Factor 1/pharmacology , Neuroprotective Agents/pharmacology , Protein Serine-Threonine Kinases , Signal Transduction , Adenoviridae/metabolism , Animals , Blotting, Western , Cell Death , Cell Line , Cell Survival , Cells, Cultured , Cytoskeletal Proteins/metabolism , DNA Fragmentation , Fibroblast Growth Factor 1/metabolism , Genetic Vectors , Glutamic Acid/metabolism , Glycogen Synthase Kinase 3 , Glycogen Synthase Kinases , Heparin Lyase/metabolism , Humans , Immunohistochemistry , Microscopy, Confocal , Microscopy, Fluorescence , Models, Biological , Neurons/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Rats , Recombinant Proteins/metabolism , Serine/metabolism , Time Factors , Trans-Activators/metabolism , beta Catenin
2.
J Neurosci Res ; 67(3): 379-87, 2002 Feb 01.
Article in English | MEDLINE | ID: mdl-11813243

ABSTRACT

The association of the E4 allele of apolipoprotein E (apoE4) as a genetic risk factor for Alzheimer's disease (AD) has been well established. Although recent studies in neuronal cell lines and transgenic mice have shown that apoE4 promotes neurodegeneration, the mechanisms through which apoE4 impairs neuronal viability are not completely understood. In this context, the main objective of the present study was to determine whether the neurotoxic effects of apoE4 are mediated by an alteration in calcium homeostasis. For this purpose, effects of recombinant apoE3 and apoE4 on cell viability and intracellular calcium levels were analyzed in a murine hippocampal cell line (HT22) and in primary rat cortical neurons, in the presence or absence of calcium inhibitors. Under basal conditions, apoE4-treated cells displayed increased levels of cytosolic calcium associated with cell death in a dose-dependent manner. Furthermore, apoE4 treatment potentiated the rise in cytosolic calcium and cell death following the administration of a calcium ionophore. The effects of apoE4 on cell viability and calcium homeostasis were inhibited by calcium chelators or by blocking calcium channels, but not by inhibitors of intracellular calcium reserves. Taken together, these results indicate that the neurotoxic effects of apoE4 are dependent on extracellular calcium influx via calcium channels.


Subject(s)
Apolipoproteins E/toxicity , Calcium/metabolism , Homeostasis/drug effects , Neurons/drug effects , Neurons/metabolism , Animals , Apolipoprotein E4 , Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Cell Membrane/metabolism , Cell Survival/drug effects , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Chelating Agents/pharmacology , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/metabolism , Ionophores/pharmacology , LDL-Receptor Related Protein-Associated Protein/pharmacology , Low Density Lipoprotein Receptor-Related Protein-1/antagonists & inhibitors , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Mice , Neurons/cytology , Rats
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