A Single Trapped Vesicle Enhances the Sensing of Dynamic in-Teractions between Tau Protein and Lipid Membrane

The interaction between tau protein and lipid membrane is of considerable interest in neuroscience, as it promotes inter-neuronal tau spreading in neurodegenerative diseases. Here, we report a vesicle-enhanced nanopore electrochemistry for sensing the dynamic lipid-tau interaction at a sub-millisecond time scale. This method is developed by confining a model vesicle of ~ 30 nm within a lipid-modified nanopipette orifice with a comparable diameter, which increases the sensing ability in lipid-tau interaction to a signal-to-noise ratio of 10.8. Both tau and phosphorylated tau present a periodic dynamic behavior in this biomimetic system, showing typical ionic current oscillation. By comparing the oscillation frequency, p-tau shows a higher affinity to the lipid vesicles, considering its lowered binding frequency towards vesicle. This result is also supported by the Biolayer interferometry. For this well-distributed current oscillation, we proposed volume shrinking as a possible mechanism, which is further supported by finite element simulations. To elucidate the possibility of lipid-tau interactions inducing vesicle shrinkage, TEM was employed for vesicle characterization in bulk solution. With a 14 h incubation of SUV with tau proteins, the diameter shrunk from ~30 nm to ~22 nm. The difference of affinity between tau and p-tau toward synaptic-mimic vesicles helps to provide fundamental insight into the regulation of tau proteins in synaptic vesicle motility and consequently contributes to the understanding of neural dysfunction in neuro-degenerative diseases. Figure 1