Altered Cytoskeletal Composition and Delayed Neurite Elongation in tau45–230-Expressing Hippocampal Neurons

Abstract

Calpain-mediated tau cleavage into the neurotoxic tau45–230 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 tau45–230 associates with the cytoskeleton in hippocampal neurons. In the present study, we assessed whether such localization could underlie tau45–230 neurotoxic effects. Quantitative Western blot analysis showed decreased levels of full-length tau bound to microtubules in tau45–230-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 tau45–230-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 tau45–230 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.