Microtubule binding and trapping at the tip of neurites regulate tau motion in living neurons

CARINA WEISSMANN; HANS-JÜRGEN REYHER; ANNE GAUTHIER; HEINZ-JÜRGEN STEINHOFF; WOLFGANG; ROLAND BRANDT

Traffic journal The International Journal of Intracellular Transport

Wiley interscience

Año: 2009

1398-9219

During the development of neurons the microtubule-associated tau proteins show a graded proximo-distal distribution in axons. In tauopathies such as Alzheimer's disease tau accumulates in the somatodendritic compartment. To scrutinize the determinants of tau's distribution and motion, we constructed photoactivatable GFP-tagged tau fusion proteins and recorded their distribution after focal activation in living cells. Simulation showed that the motion of tau was compatible with diffusion/reaction as opposed to active transport/reaction. Effective diffusion constants of 0.7-0.8 £gm2/s were calculated in neurites of PC12 cells and primary cortical neurons. Furthermore, tau's aminoterminal projection domain mediated binding and enrichment of tau at distal neurites indicating that the tip of a neurite acts as an adsorber trapping tau protein. Treatment with taxol, incorporation of diseaserelated tau modifications, experimentally induced hyperphosphorylation and addition of preaggregated amyloid £]ƒn peptides (A£]) increased the effective diffusion constant compatible with a decreased binding to microtubules. Distal enrichment was present after taxol treatment, but was suppressed at disease-relevant conditions. The data suggest that (i) dynamic binding of tau to microtubules and diffusion along microtubules and (ii) trapping at the tip of a neurite both contribute to its distribution during development and disease.2/s were calculated in neurites of PC12 cells and primary cortical neurons. Furthermore, tau's aminoterminal projection domain mediated binding and enrichment of tau at distal neurites indicating that the tip of a neurite acts as an adsorber trapping tau protein. Treatment with taxol, incorporation of diseaserelated tau modifications, experimentally induced hyperphosphorylation and addition of preaggregated amyloid £]ƒn peptides (A£]) increased the effective diffusion constant compatible with a decreased binding to microtubules. Distal enrichment was present after taxol treatment, but was suppressed at disease-relevant conditions. The data suggest that (i) dynamic binding of tau to microtubules and diffusion along microtubules and (ii) trapping at the tip of a neurite both contribute to its distribution during development and disease.£]ƒn peptides (A£]) increased the effective diffusion constant compatible with a decreased binding to microtubules. Distal enrichment was present after taxol treatment, but was suppressed at disease-relevant conditions. The data suggest that (i) dynamic binding of tau to microtubules and diffusion along microtubules and (ii) trapping at the tip of a neurite both contribute to its distribution during development and disease.