It is widely accepted that synaptic dysfunction contributes to the pathology of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease. Synaptic vesicles (SVs), with diameters ranging from several tens to hundreds of nanometers, are generally involved in the binding to tau proteins. Recent neuroscience research has shown that neurotransmitter release could be regulated by tau via the interaction with synaptic vesicles. Increasing evidence indicates that tau could bind to SVs via its N-terminal domain, which further alters the properties of synaptic function, including synaptic vesicle mobility and release rate, thus blocking neuronal communication. However, little is known about how the tau protein affects synaptic vesicle dynamics or the unrevealed mechanism of extracellular tau toxicity. Therefore, investigating the regulation of tau proteins towards SV dynamics especially in the complex membrane environment, is of great significance.
We report an electrochemical method using a synapse-mimicking nanopipette to monitor vesicle dynamics induced by tau. A model vesicle of ~30 nm is confined within a lipid-modified nanopipette orifice with a comparable diameter to mimic the synaptic lipid environment. Both tau and phosphorylated tau (p-tau) present two-state dynamic behavior in this biomimetic system, showing typical ionic current oscillation, induced by lipid-tau interaction. The results indicate that p-tau has a stronger affinity to the lipid vesicles in the confined environment, blocking the vesicle movement to a higher degree. Taken together, this method bridges a gap for sensing synaptic vesicle dynamics in a confined lipid environment, mimicking vesicle movement near the synaptic membrane. These findings contribute to understanding how different types of tau protein regulate synaptic vesicle motility and to underlying its functional and pathological behaviour in disease.
The related paper entitled “Electrochemical Monitoring of Real-Time Vesicle Dynamics Induced by Tau in a Confined Nanopipette” has been published on Angewandte Chemie International Edition on July 31, 2024 (Paper link: https://doi.org/10.1002/anie.202406677). Prof. Yi-Tao Long is the co-corresponding author. PhD. student Ke-Le Chen is the first authors. Prof. Andrew G. Ewing in Gothenburg University provided important guidance in vesicle dynamics model and Prof. Peng Zheng offered significant guidance in AFM experiments. This research was supported by the National Natural Science Foundation of China, NSFC-STINT Mobility Programme and Excellent Research Program of Nanjing University.
Fig. 1 Synapse-mimicking nanopipette for sensing the vesicle dynamics and current traces for tau-induced vesicle dynamics.
Fig. 2 Electrochemical monitoring of vesicle dynamics induced by tau and p-tau and corresponded protein affinity towards lipid.