1. Tau oligomers impair memory and synaptic plasticity through the cellular prion protein
Key Findings Tau oligomers (TauOs) are strongly implicated in Alzheimer’s disease (AD) and other tauopathies; their levels correlate with disease severity better than neurofibrillary tangles. Cellular prion protein (PrPC) mediates the toxic effects of TauOs on memory and synaptic plasticity. Wild-type mice injected intracerebroventricularly with TauOs showed impaired recognition memory and reduced long-term potentiation (LTP). PrPC knockout (Prnp⁰/⁰) mice were protected — TauOs did not impair memory or LTP in these animals. Surface plasmon resonance (SPR) demonstrated direct, high-affinity binding between TauOs and PrPC (KD ~20–50 nM). Cell studies (HEK293 vs. PrPC-overexpressing HEK293) showed PrPC-dependent TauO binding and internalization; co-localization occurred on the plasma membrane and in intracellular compartments. Tau monomers (TauM) did not cause the same detrimental effects or bind PrPC with the same affinity. Hypothesis Core Mechanism C...