The transcription factor STAT3 has a crucial role in the development and maintenance of the nervous system. In this work, we treated astrocytes with oligomers of the amyloid beta peptide (AÎ²Os), which display potent synaptotoxic activity, and studied the effects of mediators released by AÎ²Os-treated astrocytes on the nuclear location of neuronal serine-727-phosphorylated STAT3 (pSerSTAT3). Treatment of mixed neuron-astrocyte cultures with 0.5 µM AÎ²Os induced in neurons a significant decrease of nuclear pSerSTAT3, but not of phosphotyrosine-705 STAT3, the other form of STAT3 phosphorylation. This decrease did not occur in astrocyte-poor neuronal cultures revealing a pivotal role for astrocytes in this response. To test if mediators released by astrocytes in response to AÎ²Os induce pSerSTAT3 nuclear depletion, we used conditioned medium derived from AÎ²Os-treated astrocyte cultures. Treatment of astrocyte-poor neuronal cultures with this medium caused pSerSTAT3 nuclear depletion but did not modify overall STAT3 levels. Extracellular catalase prevented the pSerSTAT3 nuclear depletion caused by astrocyte-conditioned medium, indicating that reactive oxygen species (ROS) mediate this response. This conditioned medium also increased neuronal oxidative tone, leading to a ryanodine-sensitive intracellular calcium signal that proved to be essential for pSerSTAT3 nuclear depletion. In addition, this depletion decreased BCL2 and Survivin transcription and significantly increased BAX/BCL2 ratio. This is the first description that ROS generated by AÎ²Os-treated astrocytes and neuronal calcium signals jointly regulate pSerSTAT3 nuclear distribution in neurons. We propose that astrocytes release ROS in response to AÎ²Os, which by increasing neuronal oxidative tone, generate calcium signals that cause pSerSTAT3 nuclear depletion and loss of STAT3 protective transcriptional activity.