Aims

Tau is involved in maintaining neuronal structure. In tauopathies, tau can aggregate to form oligomers (oTau). Although the toxicity of oTau is well established, the mechanistic basis of its actions on neuronal function remains poorly understood. Previously, full-length recombinant oTau was found to disrupt neuronal function, synaptic transmission and plasticity (Hill et al, 2019). In this study, we look to understand how oTau mediates these changes.

Methods

We truncated the tau molecule into two parts: the first 123 amino acids and the remaining 124-441 amino acids. We have used these clinically relevant truncations to elucidate the mechanisms underlying the changes in neuronal properties. We introduced the truncated versions of tau in aggregated form into single hippocampal pyramidal cells in acute mouse brain slices and measured the resultant changes in neuronal properties.

Results

These truncated tau molecules had specific effects on neuronal function, allowing us to assign the actions of full-length tau to different regions of the molecule. We identified one key target for the effects of tau, the voltage-gated sodium channel, which could account for the effects of tau on action potential waveform.

Conclusions

This simple, yet highly effective technique of introducing structurally defined aggregated proteins into single neurons allows unparalleled levels of detail and provides a unique opportunity to understand the underlying pathology for tauopathies. By truncating the tau molecule, we have probed the mechanisms that underlie tau dysfunction, and this increased understanding of tau’s pathological actions will build towards developing future tau-targeting therapies.

Hill et al (2019). eNeuro, 6(5), pp.eNEURO.0166-19.2019.