Virus-mediated tau aggregate seeding in a cellular model

Formation of neuronal tau protein aggregates is a defining feature of tauopathies, including Alzheimer’s disease and frontotemporal dementia. Tau pathology propagates across brain regions by a cell-to-cell aggregate seeding mechanism. While epidemiological and experimental studies over the past three decades have implicated viral infections in aggregate-associated neurodegeneration, the underlying mechanisms remain unclear. Here, we show in a cell culture model that seeding competent tau aggregates are efficiently packaged into lentiviral particles and induce tau aggregation in recipient cells in a virus receptor-dependent manner. Tau aggregates interact with the viral Gag polyprotein, likely facilitating their incorporation into virions. Virus-dependent tau seeding requires protease-mediated maturation of the envelope protein to enable efficient fusion of the viral envelope with the plasma membrane of the recipient cell. Thus, tau aggregate packaging is compatible with the formation of mature, infectious virions. These findings are consistent with a possible role of viral infection in neurodegenerative disease progression and offer a robust, versatile platform to model tau propagation in cellular systems and animal models.