Role of prion protein in mediating the synaptotoxic effects of tau oligomers: Implications for Alzheimer’s disease and related tauopathies

Topic: Brain proteins, microglia and lab models

We recently confirmed and extended these findings using recombinant TauOs generated from full-length human tau in the presence of arachidonic acid (Balducci et al., 2025; Figure 1). Furthermore, intracerebroventricular injection of TauOs significantly impaired recognition memory in wild-type, but not in PrPC knockout mice, providing the first direct evidence of a PrPC-dependent effect of TauOs on cognitive function in vivo.Figure 1: Cellular prion protein (PrP C ) mediates the toxic activities of tau oligomers.Left: Tau oligomers (TauOs), but not monomers (TauM), inhibit long-term potentiation (LTP) in hippocampal slices and impair memory in PrP-expressing wild-type (WT) mice. Together, these findings support the concept that PrPC mediates the synaptotoxic effects of tau oligomers through a direct interaction. It will be crucial to validate these findings using well-characterized TauOs purified from the brains of patients with AD and other tauopathies, such as frontotemporal dementia, progressive supranuclear palsy, and chronic traumatic encephalopathy. Together these findings raise the intriguing possibility that the TauO-PrPC complex may be internalized and recycled via low-density lipoprotein receptor-related protein 1, thereby contributing to tau propagation. A deeper understanding of the molecular mechanisms underlying TauO toxicity in relation to PrPC could significantly advance the development of effective strategies for preventing and treating AD and other neurodegenerative conditions characterized by tau misfolding and oligomerization.

Key findings

• We recently confirmed and extended these findings using recombinant TauOs generated from full-length human tau in the presence of arachidonic acid (Balducci et al., 2025; Figure 1).
• Furthermore, intracerebroventricular injection of TauOs significantly impaired recognition memory in wild-type, but not in PrPC knockout mice, providing the first direct evidence of a PrPC-dependent effect of TauOs on cognitive function in vivo.Figure 1: Cellular prion protein (PrP C ) mediates the toxic activities of tau oligomers.Left: Tau oligomers (TauOs), but not monomers (TauM), inhibit long-term potentiation (LTP) in hippocampal slices and impair memory in PrP-expressing wild-type (WT) mice.
• Together, these findings support the concept that PrPC mediates the synaptotoxic effects of tau oligomers through a direct interaction.
• It will be crucial to validate these findings using well-characterized TauOs purified from the brains of patients with AD and other tauopathies, such as frontotemporal dementia, progressive supranuclear palsy, and chronic traumatic encephalopathy.
• Together these findings raise the intriguing possibility that the TauO-PrPC complex may be internalized and recycled via low-density lipoprotein receptor-related protein 1, thereby contributing to tau propagation.

Why it matters

In mice, tau oligomers impaired recognition memory in normal mice but not in mice lacking the cellular prion protein, supporting a role for this protein in tau oligomer toxicity. This is animal and laboratory work, and the authors say it still needs validation using tau oligomers purified from patients' brains.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.4103/nrr.nrr-d-25-00516
• PubMed: 40808392
• Original source →
• Free full text: Neural Regeneration Research →

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@article{chiesa2025-40808392,
  author  = {Chiesa, Roberto and Fioriti, Luana and Forloni, Gianluigi and Balducci, Claudia},
  title   = {{Role of prion protein in mediating the synaptotoxic effects of tau oligomers: Implications for Alzheimer’s disease and related tauopathies}},
  journal = {Neural Regeneration Research},
  year    = {2025},
  doi     = {10.4103/nrr.nrr-d-25-00516},
  pmid    = {40808392},
  url     = {https://doi.org/10.4103/nrr.nrr-d-25-00516}
}

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