The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells.

Tauopathies are prevalent, invariably fatal brain diseases for which no cure is available. Tauopathies progressively affect the brain through cell-to-cell transfer of tau protein amyloids, yet the spreading mechanisms remain unknown. Here we show that the cellular prion protein (PrP ) facilitates the uptake of tau aggregates by cultured cells, possibly by acting as an endocytic receptor. In mouse neuroblastoma cells, pull-down experiments revealed that tau amyloids bind to PrP . Confocal images of both wild-type and PrP -knockout N2a cells treated with fluorescently labeled synthetic tau fibrils showed that the internalization was reduced in isogenic cells devoid of the gene encoding PrP . Pre-treatment of the same cells with antibodies against N-proximal epitopes of PrP impaired the binding of tau amyloids and decreased their uptake. Surprisingly, exposure of chronically prion-infected cells to tau amyloids reduced the accumulation of aggregated prion protein and this effect lasted for more than 72 hr after amyloid removal. These results point to bidirectional interactions between the two proteins: while PrP mediates the entrance of tau fibrils in cells, PrP buildup is greatly reduced in their presence, possibly because of an impairment in the prion conversion process.