Tau oligomers impair memory and synaptic plasticity through the cellular prion protein

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Abnormally phosphorylated tau aggregates, particularly tau oligomers (TauOs), are central to neuronal dysfunction and death in Alzheimer's disease (AD) and other tauopathies.
• The precise mechanisms by which TauOs exert neurotoxicity remain unclear, though cellular prion protein (PrP^C) is implicated as a potential mediator.

Purpose of the Study:

• To investigate whether PrP^C mediates the detrimental effects of TauOs on memory and synaptic plasticity.
• To determine if a direct interaction exists between TauOs and PrP^C.

Main Methods:

• Comparison of TauO effects on recognition memory and long-term potentiation in wild-type (WT) and PrP^C knockout (Prnp^0/0) mice.
• Surface plasmon resonance to assess TauO-PrP^C binding affinity.
• Immunofluorescence analysis to evaluate TauO association with PrP^C-expressing cells.

Main Results:

• TauOs impaired recognition memory and long-term potentiation in WT mice, but not in Prnp^0/0 mice.
• High-affinity binding (K_D of 20-50 nM) was observed between TauOs and PrP^C.
• TauOs showed PrP^C dose-dependent association with cells and co-localization with PrP^C.

Conclusions:

• PrP^C mediates the neurotoxic effects of TauOs through direct interaction.
• Targeting the PrP^C-TauO interaction represents a potential therapeutic strategy for AD and tauopathies.