Modeling tau transport in the axon initial segment

TL;DR

This paper presents the first mathematical model of tau protein transport in the axon initial segment, revealing how diffusion and motor-driven mechanisms collaborate to move tau into the axon.

Contribution

The study introduces a novel kinetic model of tau transport in the AIS, calibrated with experimental data, highlighting the interplay of diffusion and motor-driven transport mechanisms.

Findings

Tau binding to microtubules creates a negative gradient in the AIS.

Diffusion-driven tau transport occurs from the soma into the AIS.

Transport mechanisms shift from diffusion to motor-driven as distance increases.

Abstract

By assuming that tau protein can be in seven kinetic states, we developed a model of tau protein transport in the axon and in the axon initial segment (AIS). Two separate sets of kinetic constants were determined, one in the axon and the other in the AIS. This was done by fitting the model predictions in the axon with experimental results and by fitting the model predictions in the AIS with the assumed linear increase of the total tau concentration in the AIS. The calibrated model was used to make predictions about tau transport in the axon and in the AIS. To the best of our knowledge, this is the first paper that presents a mathematical model of tau transport in the AIS. Our modeling results suggest that binding of free tau to MTs creates a negative gradient of free tau in the AIS. This leads to diffusion-driven tau transport from the soma into the AIS. The model further suggests that slow axonal transport and diffusion-driven transport of tau work together in the AIS, moving tau anterogradely. Our numerical results predict an interplay between these two mechanisms: as the distance from the soma increases, the diffusion-driven transport decreases, while motor-driven transport becomes larger. Thus, the machinery in the AIS works as a pump, moving tau into the axon.