Why slow axonal transport is bidirectional – can axonal transport of tau protein rely only on motor-driven anterograde transport?

Slow axonal transport (SAT) moves multiple proteins from the soma, where they are synthesized, to the axon terminal. Due to the great lengths of axons, SAT almost exclusively relies on active transport, which is driven by molecular motors. The puzzling feature of slow axonal transport is its bidirectionality. Although the net direction of SAT is anterograde, from the soma to the terminal, experiments show that it also contains the retrograde component. One of the proteins transported by SAT is microtubule-associated protein tau. To better understand why the retrograde component in tau transport is needed, we used the perturbation technique. We analyzed the simplification of the full tau SAT model for the case when retrograde motor-driven transport and diffusion-driven transport of tau are negligible, and tau is driven only by anterograde (kinesin) motors. We obtained an analytical solution of the simplified equations. The solution of the simplified equations shows that the tau concentration along the axon length stays almost uniform (decreases very slightly). This is explained as follows. In the case of anterograde-only motor-driven transport, the tau concentration is determined by the tau flux from the soma to the axon (the inlet condition) and by the events occurring during tau transport, such as tau degradation. However, the tau concentration in the axon cannot reflect the tau concentration at the outlet boundary (at the terminal). Consequently, kinesin-driven transport alone cannot achieve the tau concentration required at the terminal. A transport mechanism that is supplemental to the kinesin-driven transport is needed. In mathematical terms, a mechanism for retrograde transport of tau is necessary for the information about the value that the tau concentration must take in the downstream segment of the axon to be transmitted upstream. This may explain the presence of the retrograde motor-driven component in SAT.