ANTISENSE STRATEGY UNRAVELS TAU-PROTEINS AS MOLECULAR RISK-FACTORS FOR GLUTAMATE-INDUCED NEURODEGENERATION

1. We investigated the possible involvement of tau proteins in the neu rotoxic process activated by glutamate using the oligonucleotide antis ense strategy, 2. We found that pretreatment of granule cells with an antisense oligonucleotide of the tau gene completely prevented the inc rease in tau immunoreactivity induced by glutamate, 3. A significant a mount of the tau antisense oligonucleotide (about 1 to 2% of total) wa s taken up by the cells and remained stable in the cells for at least 60 min, A dose-response study revealed that 25 mu M tau antisense olig onucleotide was the most efficacious concentration in terms of prevent ion of glutamate-induced tau immunoreactivity increases, without affec ting basal tau expression, Higher concentrations of tau oligonucleotid e antisense reduced tau immunoreactivity in control cells, 4. Signific antly, the concentration-response curve of glutamate for inducing neur onal death in cells pretreated with tau antisense oligonucleotide show ed a shift to the right compared to those obtained in untreated or tau sense oligonucleotide-treated cells. 5. Since inhibition of tau synth esis does not completely prevent but only decreases the neuronal sensi tivity to glutamate, it is tempting to speculate that accumulation of tau within the neuron in response to glutamate represents one of the m olecular risk factors lowering the safety margin of neurons to excitot oxic-induced injury.