Glial fibrillary tangles and JAK/STAT-mediated glial and neuronal cell death in a Drosophila model of glial tauopathy.

A subset of neurodegenerative tauopathies is characterized by abundant filamentous inclusions of hyperphosphorylated tau in both neurons and glia. Although the contribution of neuronal tau to behavioral changes and neuronal loss in neurodegenerative diseases has been studied extensively, the functional consequences of tau deposition in glial cells have been less well characterized. To investigate the role of abnormal tau accumulation and aggregation in glial cells, we created a Drosophila model of glial tauopathy by expressing human wild-type tau in adult fly glial cells. Glial expression of tau resulted in robust aggregation of phosphorylated tau into fibrillary inclusions similar to human glial tangles. Tangle formation was accompanied by shortened lifespan and age-dependent apoptotic cell death of both glia and neurons. Genetic manipulation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling modified toxicity of glial tau. We also identified a synergistic interaction of combined tau expression in neurons and glial cells. In summary, we present a genetically tractable model of glial fibrillary tau tangle formation and identify JAK/STAT signaling as mediating the death of both glia and neurons in this model.