摘要Progressive aggregation of tau protein in neurons is associated with neurodegeneration in tauopathies.Cell non-autonomous disease mechanisms in astrocytes may be important drivers of the disease process but remain largely elusive.Here,we studied cell type-specific responses to intraneuronal tau aggregation prior to neurodegeneration.To this end,we developed a fully human co-culture model of seed-independent intraneuronal tau pathology,which shows no neuron and synapse loss.Using high-content microscopy,we show that intraneuronal tau aggregation induces oxidative stress accompanied by activation of the integrated stress response specifically in astrocytes.This requires the direct co-culture with neurons and is not related to neurodegeneration or extracellulartau levels.Tau-directed antisense therapy reduced intraneuronal tau levels and aggregation and prevented the cell non-autonomous responses in astrocytes.These data identify the astrocytic integrated stress response as a novel disease mechanism activated by intraneuronal tau aggregation.In addition,our data provide the first evidence for the efficacy of tau-directed antisense therapy to target cell autonomous and cell non-autonomous disease pathways in a fully human model of tau pathology.