PRNP基因敲除HEK293细胞

Deposition of abnormally phosphorylated tau aggregates is a central event leading to neuronal dysfunction and death in Alzheimer's disease (AD) and other tauopathies. Among tau aggregates, oligomers (TauOs) are considered the most toxic. AD brains show significant increase in TauOs compared to healthy controls, their concentration correlating with the severity of cognitive deficits and disease progression. In vitro and in vivo neuronal TauO exposure leads to synaptic and cognitive dysfunction, but their mechanisms of action are unclear. Evidence suggests that the cellular prion protein (PrP) may act as a mediator of TauO neurotoxicity, as previously proposed for β-amyloid and α-synuclein oligomers. To investigate whether PrP mediates TauO detrimental activities, we compared their effects on memory and synaptic plasticity in wild type (WT) and PrP knockout (Prnp) mice. Intracerebroventricular injection of TauOs significantly impaired recognition memory in WT but not in Prnp mice. Similarly, TauOs inhibited long-term potentiation in acute hippocampal slices from WT but not Prnp mice. Surface plasmon resonance indicated a high-affinity binding between TauOs and PrP with a K of 20-50 nM. Immunofluorescence analysis of naïve and PrP-overexpressing HEK293 cells exposed to TauOs showed a PrP dose-dependent association of TauOs with cells over time, and their co-localization with PrP on the plasma membrane and in intracellular compartments, suggesting PrP-may play a role in TauO internalization. These findings support the concept that PrP mediates the detrimental activities of TauOs through a direct interaction, suggesting that targeting this interaction might be a promising therapeutic strategy for AD and other tauopathies.