Premium
O1‐06–05: Swimming against the tide: Mechanisms of Tau distribution in neurons
Author(s) -
Mandelkow Eckhard,
Konzack Sven,
Thies Edda,
Marx Alexander,
Mandelkow Eva-Maria
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.260
Subject(s) - fluorescence recovery after photobleaching , microtubule , axoplasmic transport , biophysics , chemistry , cytoplasmic streaming , filopodia , live cell imaging , neuroscience , microbiology and biotechnology , biology , cell , cytoplasm , biochemistry , membrane
Background: Tau is normally an axonal protein that helps to stabilize microtubules. In Alzheimer’s disease, tau redistributes to the somatodendritic compartment. Elevated tau can cause traffic inhibition in neurons by obstructing microtubules, the tracks of intracellular transport. The inhibition affects mainly the anterograde traffic, leading to a net flowof particles (vesicles, organelles) back to the cell body. In spite of this net backward flow, tau itself can move anterogradely and thus can apparently “swim against the tide”. Methods: We are analyzing this seeming contradiction by transfecting neuronal cell cultures with tau and observing its behavior by live-cell fluorescence microscopy, fluorescence recovery after photobleaching (FRAP), and fluorescence speckle microscopy (FSM). Results: We found that one reason for tau’s distribution is its unusually high mobility in the cytosol, with a diffusion-coefficient of 3 m/s and a dwell-time on microtubules of only 4sec. Thus, even though tau is a microtubule-associated protein, it can bind and dissociate rapidly and frequently. This property facilitates the entry of tau into axons more efficiently than directed transport over fairly long distances (millimeters) and periods (days). For longer distances and time periods tau is cotransported with microtubule fragments from cell bodies into axons, moving at instantaneous velocities 1 m/s interrupted by pauses (reminiscent of slow axonal transport). Conclusions: Thus, the somatodendritic accumulation of tau in AD neurons can be explained by a high diffusion rate, coupled with blockage of anterograde axonal transport. Supported by MPG and DFG.