The study investigates the differential regulation of dynein and kinesin motor proteins by tau, a microtubule-associated protein (MAP) abundant in neurons. Using single-molecule studies, the researchers found that dynein tended to reverse direction upon encountering tau, while kinesin was more likely to detach from tau-decorated microtubules. Kinesin was inhibited at a lower tau concentration than dynein, and the microtubule-binding domain of tau was sufficient to inhibit motor activity. The findings suggest that MAPs can spatially regulate the balance of microtubule-dependent axonal transport, with tau potentially controlling the distribution of kinesin and dynein along axons to maintain proper transport dynamics. This regulation is crucial for cell function and may contribute to neurodegenerative diseases like Alzheimer's.The study investigates the differential regulation of dynein and kinesin motor proteins by tau, a microtubule-associated protein (MAP) abundant in neurons. Using single-molecule studies, the researchers found that dynein tended to reverse direction upon encountering tau, while kinesin was more likely to detach from tau-decorated microtubules. Kinesin was inhibited at a lower tau concentration than dynein, and the microtubule-binding domain of tau was sufficient to inhibit motor activity. The findings suggest that MAPs can spatially regulate the balance of microtubule-dependent axonal transport, with tau potentially controlling the distribution of kinesin and dynein along axons to maintain proper transport dynamics. This regulation is crucial for cell function and may contribute to neurodegenerative diseases like Alzheimer's.