Dynamic regulation of expression and phosphorylation of tau by fibroblast growth factor-2 in neural progenitor cells from adult rat hippocampus.
The nature of the extracellular signals that regulate the expression and the phosphorylation of the microtubule-associated protein tau, which is aberrantly hyperphosphorylated in Alzheimer disease and other adult-onset neurodegenerative diseases, is not known. We have found that neural progenitor cells from adult rat hippocampus express adult isoforms of tau and that the expression and the phosphorylation of tau are regulated by fibroblast growth factor-2 (FGF-2). Astrocytes that are differentiated from these cells by stimulation with ciliary neurotrophic factor express phosphorylated tau similarly when cultured in the presence of FGF-2. In fetal progenitor cells that express only the fetal tau isoform, expression, but not the phosphorylation, of this protein is regulated by FGF-2 in cultures of higher passages. The FGF-2-mediated tau hyperphosphorylation is inhibited by lithium, an inhibitor of glycogen synthase kinase-3 (GSK-3), but not by inhibitors of mitogen-activated protein kinase or the cyclin-dependent kinases. Furthermore, both GSK-3 activity and the phosphorylation of tau increase when the concentration of FGF-2 is increased up to 40 ng/ml. These results demonstrate that proliferating adult rat hippocampal progenitor cells express adult isoforms of tau stably and that FGF-2 upregulates the expression and, by upregulating GSK-3 activity, the phosphorylation of tau.
Tatebayashi
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New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.
Iqbal
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Grundke-Iqbal
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D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006624:Hippocampus / Q000166:cytology* / Q000196:embryology; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D064231:Nestin; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D016875:tau Proteins / Q000378:metabolism*
D020934:Ciliary Neurotrophic Factor; D007381:Intermediate Filament Proteins; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D020033:Protein Isoforms; D014404:Tubulin; D016875:tau Proteins; D016222:Fibroblast Growth Factor 2; D012694:Serine; D008094:Lithium; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3