The human circular Tau 12->7 RNA is translated in mouse neurons and promotes tau aggregation

In addition to numerous mRNA isoforms, the human microtubule associated protein tau (MAPT) gene generates circular RNAs that are not known to be expressed in rodents. Using adeno associated viruses, we expressed human circular Tau RNA generated from backsplicing of exon 12 to exon 7 (circTau 12->7) in mouse brain. We observed rolling circle translation of circTau 12->7, similar to cultured human HEK293 cells. Despite using a ubiquitously active promoter, circTau 12->7 protein and a control circEGFP protein were only observed in mouse neurons, indicating neuron-specific translation of these circular RNAs. CircTau 12->7 expression resulted in tau aggregates resembling neurofibrillary tangles in mouse brain that included endogenous mouse tau protein. Our data support a model where neuron-specific translation of circTau RNAs induces 'linear', mRNA-translated tau aggregation, which could contribute to tauopathies, including Alzheimer's disease. Thus, targeting circTau RNAs could be a therapeutic approach for Alzheimer's disease.