Variable tau accumulation in murine models with abnormal prion protein deposits

Area of Science:

• Neuroscience
• Pathology
• Biochemistry

Background:

• Prion diseases involve the misfolding of cellular prion protein (PrP).
• Heterogeneous prion disease phenotypes may relate to co-occurring misfolded proteins, such as hyperphosphorylated tau (p.tau).
• p.tau is a hallmark of Alzheimer's disease (AD) but also appears in human prion diseases.

Purpose of the Study:

• To investigate the association between prion protein (PrP) misfolding and hyperphosphorylated tau (p.tau) formation in mouse models.
• To differentiate the role of prion infectivity versus PrP amyloid deposition in p.tau generation.

Main Methods:

• Immunohistochemical analysis of p.tau and PrP in mouse models.
• Comparison between mice inoculated with prion agents and mice with PrP amyloid in the absence of prion disease.

Main Results:

• p.tau was consistently detected in mice with prion infectivity (transmissible disease models).
• p.tau was rarely observed or absent in mice with PrP amyloid plaques but without prion replication.
• PrP amyloid deposition alone did not induce p.tau formation.

Conclusions:

• p.tau formation in prion disease is linked to prion replication, not solely to misfolded PrP deposition.
• The interaction between prion replication and host factors likely regulates p.tau formation.
• This interaction may contribute to the diverse clinical presentations of prion diseases.