Tau45-230 association with the cytoskeleton and membrane-bound organelles: Functional implications in neurodegeneration

•The neurotoxic tau45-230 associates both microtubules and membrane-bound organelles in hippocampal neurons.•These associations are independent of the presence of full-length tau.•Tau45-230 impairs anterograde and retrograde axonal transport.•Defects in organelle transport are not associated with changes in motor protein levels.

The dysregulation of posttranslational modifications of the microtubule-associated protein (MAP) tau plays a key role in Alzheimer's disease (AD) and related disorders. Thus, we have previously shown that beta amyloid (Aβ)-induced neurotoxicity was mediated, at least in part, by tau cleavage into the tau45-230 fragment. However, the mechanisms underlying the toxicity of tau45-230 remain unknown. To get insights into such mechanisms, we first determined the subcellular localization of this tau fragment in hippocampal neurons. Tau45-230 was easily detectable in cell bodies and processes extended by these neurons. In addition, cell extraction experiments performed using Triton X-100 and saponin showed that a pool of tau45-230 was associated with the cytoskeleton and the cytoskeleton plus membrane-bound organelles, respectively, in cultured hippocampal neurons. Furthermore, they suggested that these associations were independent of the presence of full-length tau. We also assessed whether this tau fragment could alter axonal transport. Our results indicated that tau45-230 significantly reduced the number of organelles transported along hippocampal axons. This altered axonal transport did not correlate with changes in the total number of organelles present in these cells or in motor protein levels. Together these results suggested that tau45-230 could exert its toxic effects by partially blocking axonal transport along microtubules thus contributing to the early pathology of AD.