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 extracellular tau 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.
Original languageEnglish
Article numbermjac071
Pages (from-to)1-19
Number of pages19
JournalJournal of molecular cell biology
Issue number10
Early online date15 Dec 2022
Publication statusPublished - 29 Mar 2023


  • antisense oligonucleotides
  • astrocytes
  • hiPSC-derived neurons
  • integrated stress response
  • oxidative stress
  • tau aggregation

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