Alzheimer’s disease (AD) is the most common tauopathy, taking millions of lives every year. AD is characterized by the deposition of aggregates of hyperphosphorylated Tau protein and amyloid-β peptide (Aβ) in the brain. The oligomeric forms of Tau and Aβ are considered to be the neurotoxic species responsible for neurodegenerative processes in AD. Previously, we demonstrated the inhibition of the large-conductance calcium-activated potassium channel (BKCa) of mitochondria by the aggregates and oligomers of Aβ. In this study we investigated the effect of Tau oligomers on the plasma membrane BKCa activity. Furthermore, since prion protein (PrP) interacts with Tau and the N-terminal fragment of PrP, called N1, can be neuroprotective in tauopathies, we decided to check whether N1 can also act at the level of BKCa. To obtain the oligomers of Tau we used its aggregation-prone fragment (K18) carrying tauopathy-associated mutation – deletion of Lys280 (K18Δ280). Additionally, to induce oligomerization, K18Δ280 was phosphorylated by protein kinase A. The studies were carried out on a primary culture of rat hippocampal neurons. The preformed K18Δ280 oligomers were incubated in the presence or absence of N1 fragment of PrP (for 15 min) immediately prior applying. The activity of the neuronal plasma membrane BKCa was recorded using single-channel patch-clamp technique in both the „inside-” and „outside-out” modes. K18Δ280 oligomers were added directly to the recording chamber. In all experiments, the oligomers were used at 10 pM – 100 nM concentrations. The research was performed in compliance with EU and national legal and ethical requirements: EU Directive 2010/63/EU, Act of 15 January 2015 of the Ministry of Science and Higher Education of Poland. We found that, in the case of the „inside-out” patch-clamp configuration on -40mV, the open probability (Po) of the BKCa was not significantly affected by the K18Δ280 oligomers alone or after their combination with N1. Сontrariwise, performing the extracellular application of the oligomers („outside-out”), significant and concentration-dependent inhibition of BKCa was observed. For example, in the control conditions (the probe without the oligomers) on +40mV the Po of the channel was equal to 0.36±0.02 (n=35). After incubation with the highest concentration of the oligomers this indicator dropped to 0.27±0.03 (n=25) which consisted 76±8% of the control (P=0.0083). The Po of BKCa was fully recovered after washing the oligomers out: 0.39±0.05 (n=17), that is 114±13% from the control, or 168±17% from the 100 nM of K18Δ280 (P=0.0005). It is noteworthy that after incubation with N1, the oligomers lost their cytotoxicity, since they were not able to significantly inhibit BKCa. Our results suggest that N1 can convert neurotoxic oligomers of Tau into a form which is not able to inhibit BKCa channel. This effect occurs only from the extracellular side, which implies specific interaction of the oligomers with the channel. It is important from a physiological point of view, since it sheds light on the possible neuroprotective mechanism of PrP action in AD and other tauopathies.