Rescue of neurons from undergoing hallmark tau-induced Alzheimer's disease cell pathologies by the antimitotic drug paclitaxel

Abstract

Through the use of live confocal imaging, electron microscopy, and the novel cell biological platform of cultured Aplysia neurons we show that unfolding of the hallmark cell pathologies induced by mutant-human-tau (mt-human-tau) expression is rescued by 10 nM paclitaxel. At this concentration paclitaxel prevents mt-human-tau-induced swelling of axonal segments, translocation of tau and microtubules (MT) to submembrane domains, reduction in the number of MTs along the axon, reversal of the MT polar orientation, impaired organelle transport, accumulation of macro-autophagosomes and lysosomes, compromised neurite morphology and degeneration. Unexpectedly, higher paclitaxel concentrations (100 nM) do not prevent these events from occurring and in fact facilitate them. We conclude that antimitotic MT-stabilizing reagents have the potential to serve as drugs to prevent or slow down the unfolding of tauopathies.