Swimming against the tide: mobility of the microtubule-associated protein tau in neurons.

Long-haul transport along microtubules is crucial for neuronal polarity, and transport defects cause neurodegeneration. Tau protein stabilizes microtubule tracks, but in Alzheimer's disease it aggregates and becomes missorted into the somatodendritic compartment. Tau can inhibit axonal transport by obstructing motors on microtubules, yet tau itself can still move into axons. We therefore investigated tau movement by live-cell fluorescence microscopy, FRAP (fluorescence recovery after photobleaching), and FSM (fluorescence speckle microscopy). Tau is highly dynamic, with diffusion coefficients of approximately 3 microm2/s and microtubule dwell times of approximately 4 s. This facilitates the entry of tau into axons over distances of millimeters and periods of days. For longer distances and times, two mechanisms of tau transport are observed. At low near-physiological levels, tau is cotransported with microtubule fragments from cell bodies into axons, moving at instantaneous velocities approximately 1 microm/s. At high concentrations, tau forms local accumulations moving bidirectionally at approximately 0.3 microm/s. These clusters first appear at distal endings of axons and may indicate an early stage of neurite degeneration.