Intraneuronal tau pathology induces cellular stress in astrocytes in human co-culture.

Tau aggregation is the major pathological hallmark of neurodegenerative tauopathies and strongly correlates with neurodegeneration. Yet, the mechanism by which tau pathology leads to neuronal dysfunction and how astrocytes contribute to disease pathogenesis is largely elusive, partly due to the lack of suitable human co-culture models.We established a novel human neuron/astrocyte co-culture model in 96-well format, compatible with high-content automated microscopy analysis. Ngn2-iPSC differentiated neurons and primary human astrocytes were used in combination with a spontaneously aggregating tau variant.Neurons with a morphologically mature synapse pattern were obtained within 4 weeks. Introduction of a spontaneously aggregating tau variant induces progressive intraneuronal accumulation of pathologically phosphorylated, insoluble tau. Intraneuronal tau accumulation progressively induces oxidative stress and activation of the integrated stress response in co-cultured human astrocytes.This novel human co-culture model recapitulates key features of human tau pathology and enables the identification of cell autonomous and non-autonomous disease mechanisms, giving a unique opportunity for future target identification and intervention studies in a translationally relevant in vitro context.