A TAU ANTISENSE OLIGONUCLEOTIDE DECREASES NEURON SENSITIVITY TO EXCITOTOXIC INJURY

SHORT-TERM exposure of primary cultures of cerebellar granule cells fr om neonatal rat brain to high concentrations of glutamate results in n euronal degeneration. We found that glutamate, before causing neuronal degeneration, induced a significant increase of Tau protein immunosta ining. Time-course experiments revealed the increase of Tau immunoreac tivity to be maximal 2 h after the glutamate pulse. To investigate the possible role of newly synthesized Tau protein in the neurotoxic proc ess activated by glutamate, cerebellar granule cells were preincubated with a specific Tau antisense oligonucleotide. This treatment resulte d in (i) an inhibition of the glutamate-induced increase of Tau immuno reactivity and (ii) a decrease in the sensitivity of the neurones to n eurotoxic concentrations of glutamate. These data indicate that new sy nthesis of the cytoskeleton-associated Tau protein is a crucial step i n the cascade of events promoted by glutamate and leading to neurodege neration.