Introduction: Astrocytic tau aggregates are seen in several primary and secondary tauopathies, including progressive supranuclear palsy, corticobasal degeneration, and chronic traumatic encephalopathy. In all cases, astrocytic tau consists exclusively of the longer (4R) tau isoform, even when adjacent neuronal aggregates consist of a mixture of 3- and 4R tau, as in chronic traumatic encephalopathy. The reasons for this and the mechanisms by which astrocytic tau aggregates form remain unclear. Methods: We used a combination of RNA in situ hybridization and immunofluorescence in human post-mortem brain tissue and tau uptake studies in human stem-cell-derived astrocytes to determine the origins of astrocytic tau in 4R tauopathies. Results: We found that astrocytes in 4R tauopathies do not upregulate tau mRNA expression, either comparing all astrocytes between disease or tau positive- and negative astrocytes within diseases. We then found that stem-cell-derived astrocytes preferentially take up long isoform (4R) labeled recombinant tau and that this uptake is impaired by inflammation or nutritional stress. Astrocytes exposed to either 3R or 4R tau also showed downregulation of genes related to astrocyte differentiation. Discussion: Our findings suggest that astrocytes preferentially take up neuronal 4R tau from the extracellular space, which potentially explains why astrocytic tau aggregates contain only 4R tau, and that tau uptake is impaired by decreased nutrient availability or neuroinflammation, both of which are common in the aging brain.

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