PRNP and proteostasis deficiencies: To study whether p.tau deposition was associated with prion replication and neurodegeneration, or occurred as a result of PrP misfolding and aggregation we analyzed mouse models with (i) accumulation of PrPTSE either in the form of diffuse deposits or amyloid plaques that are transmissible via an infectious mechanism as shown by serial passage; and (ii) non-infectious PrP proteinopathy, in which PrP amyloid plaques are seeded in the absence of agent replication.