Distinct tau fibril types and their role in prion diseases

Neurodegenerative diseases are often characterized by the co-deposition of different amyloidogenic proteins, normally defining distinct proteinopathies. An interesting example is represented by prion diseases, in which the presence of PrPSc plaques is often accompanied by aggregates of the tau protein, normally implicated in another class of diseases called tauopathies. How this copresence of amyloidogenic proteins can influence the progression of prion disease is still a matter of debate. Recently, the cellular form of the prion protein, PrPC, has been investigated as a possible receptor of amyloidogenic proteins, since its binding activity with Aβ, tau and α-synuclein has been proved and it has been linked to several neurotoxic behaviours exerted by these proteins. In our previous paper we showed that PrPC acts as a receptor for tau K18 amyloid fibrils and that the exposure of cultured cells to these fibrils causes an increased PrPC retention at the plasma membrane. Interestingly, tau K18 fibril administration reduced PrPSc levels in chronically prion-infected cells, probably by an impairment of PrPC conversion due to the fibril binding. To deepen this aspect, we decided to exploit, together with tau K18, also another construct of tau containing the sequence forming the core of Alzheimer’s disease tau filaments in vivo. Our results suggest that, despite differing for six amino acids only, these two constructs form different tau fibril types in vitro. However, their effect on PrPSc reduction was comparable and probably based on the binding to PrPC at the plasma membrane, inhibiting the conversion event. Moreover, both amyloid fibrils were able to hinder the earlier phases of prion infection, slowing down prion replication and making cells less prone to be infected. Our results suggest PrPC as a receptor for different tau fibril types and point out a role of tau amyloid fibrils in preventing the prion conversion event at the base of the pathology. These findings may help disentangle the mutual relationship between amyloidogenic proteins that often show co-deposition.