Neurodegenerative diseases are often characterized by the co-deposition of multiple amyloidogenic proteins that typically define distinct proteinopathies.
An example is represented by prion diseases, in which the classical deposition of the misfolded prion protein isoform (PrPSc) can be associated with insoluble tau species, which are usually involved in another class of disorders known as tauopathies. How this coexistence of amyloidogenic proteins influences the progression of prion diseases remains a matter of debate.
Recently, the cellular form of the prion protein (PrPC) has been investigated as a potential receptor for amyloidogenic proteins, as it has been shown to bind Aβ, tau, and α-synuclein, and has been linked to several neurotoxic mechanisms mediated by these proteins. We previously demonstrated that treating chronically prion-infected cells with tau K18 fibrils reduced PrPSc levels.
In the present study, we further explored this mechanism using another tau construct that includes the core sequence forming tau fibrils in Alzheimer’s disease in vivo, thereby generating a distinct fibril type. Despite a six–amino acid difference, the two constructs formed fibrils with distinct biochemical and biological features. However, their effects in reducing PrPSc levels were comparable and likely relied on binding to PrPC at the plasma membrane, thereby inhibiting the pathological conversion event.
Our findings suggest that PrPC acts as a receptor for different types of tau fibrils and highlight a potential role of amyloidogenic tau fibrils in preventing the pathological conformational conversion from PrPC to PrPSc.
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