Coexpression of GSK-3β Corrects Phenotypic Aberrations of Dorsal Root Ganglion Cells, Cultured from Adult Transgenic Mice Overexpressing Human Protein tau

Coexpression of constitutively active GSK-3β[S9A] rescued the axonal pathology induced by overexpression of human tau in transgenic mice (Spittaels et al., (2000) J. Biol. Chem. 275, 41340–41349). We isolated dorsal root ganglion (DRG) neuronal cultures from adult tau4R- and tau4R × GSK-3β-transgenic mice to define the mechanisms at the cellular and subcellular level. DRG from tau4R-transgenics showed a reduced sprouting capacity while density and stability of microtubules in the axonal processes were significantly increased. Video-enhanced contrast microscopy demonstrated a dramatic inhibition of fast axonal transport. Coexpression of GSK-3β increased tau phosphorylation and reversed the effects on microtubule stability and saltatory motion. In DRG from GSK-3β single transgenics, increased tau phosphorylation was evident without any major effects on microtubule stability or axonal transport. These observations support the hypothesis that excess tau competed with motor-proteins for binding to microtubules and/or that a rigid microtubular system inhibits axonal transport.