Glutamate toxicity enhances tau gene expression in neuronal cultures.
Tau protein is a microtubule-associated protein normally expressed in neurons. In Alzheimer's disease (AD) brains, phosphorylated tau accumulates in paired helical filaments which form neurofibrillary tangles in affected neurons; moreover, tau mRNA expression is increased in affected regions of AD brains. Glutamate, an excitatory neurotransmitter but also a potent neurotoxin under pathologic conditions, is known to produce neuronal degeneration and death accompanied by an increase in tau immunoreactivity in primary neuronal cultures. The goal of the present study is to evaluate the effects of glutamate on tau gene expression in neuronal cultures. We report a delayed and long-lasting enhancement of tau mRNA expression after a 15 min exposure to toxic concentrations of glutamate: neuronal tau mRNA levels reach a peak after 3 hr and remain increased 6 and 12 hr after the end of glutamate exposure. Both NMDA and AMPA/ kainate receptors are involved in this tau gene overexpression. Actinomycin D prevents this tau mRNA induction indicating that transduction signals elicited by glutamate act at the transcriptional level. The role of this delayed tau overexpression is not elucided but could be linked to either a reactive survival process or to a programmed cellular degeneration.
Esclaire
F
F
ERS CNRS 6101, Laboratory of Histology and Cell Biology, Faculty of Medicine, Limoges, France.
Lesort
M
M
Blanchard
C
C
Hugon
J
J
D000818:Animals; D015152:Blotting, Northern; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D015342:DNA Probes; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000633:toxicity*; D015151:Immunoblotting; D017403:In Situ Hybridization; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D016875:tau Proteins / Q000096:biosynthesis* / Q000235:genetics
D015342:DNA Probes; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D016875:tau Proteins; D003609:Dactinomycin; D018698:Glutamic Acid