Altered Cytoskeletal Composition and Delayed Neurite Elongation in tau_45-230-Expressing Hippocampal Neurons

Calpain-mediated tau cleavage into the neurotoxic tau_45-230 fragment plays an important role in Alzheimer's disease (AD). This tau fragment accumulates mainly in the cytoplasm of degenerating neurons. However, subcellular localization studies indicated that a pool of tau_45-230 associates with the cytoskeleton in hippocampal neurons. In the present study, we assessed whether such localization could underlie tau_45-230 neurotoxic effects. Quantitative Western blot analysis showed decreased levels of full-length tau bound to microtubules in tau_45-230-expressing hippocampal neurons when compared to controls. In addition, the presence of this tau fragment induced a transient increase in tyrosinated tubulin, a marker of unstable microtubules, followed by a significant decrease in the levels of this tubulin isoform. The data obtained also showed a significant reduction in actin filaments in tau_45-230-expressing neurons. These changes in microtubules and actin filaments correlated with delayed neurite elongation and axonal differentiation in the presence of this tau fragment. Together, these results suggest that tau_45-230 could exert its toxic effects, at least in part, by modifying the composition of the neuronal cytoskeleton and impairing neurite elongation in neurons undergoing degeneration.