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

Abstract

<jats:title>Abstract</jats:title><jats:p>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 are unknown. Here we show that the cellular prion protein (PrP<jats:sup>C</jats:sup>) facilitates the uptake of tau aggregates by cultured cells, possibly by acting as an endocytic receptor. In mouse neuroblastoma cells, we found that tau amyloids bind to PrP<jats:sup>C</jats:sup>; internalization of tau fibrils was reduced in isogenic cells devoid of the gene encoding PrP<jats:sup>C</jats:sup>. Antibodies against N-proximal epitopes of PrP<jats:sup>C</jats:sup> 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; this effect lasted for more than 72 hours after amyloid removal. These results point to bidirectional interactions between the two proteins: whilst PrP<jats:sup>C</jats:sup> mediates the entrance of tau fibrils in cells, PrP<jats:sup>Sc</jats:sup> buildup is greatly reduced in their presence, possibly because of an impairment in the prion conversion process.</jats:p>