Curcumin improves tau-induced neuronal dysfunction of nematodes

Tau is a key protein in the pathogenesis of various neurodegenerative diseases, which are categorized as tauopathies. Because the extent of tau pathologies is closely linked to that of neuronal loss and the clinical symptoms in Alzheimer's disease, anti-tau therapeutics, if any, could be beneficial to a broad spectrum of tauopathies. To learn more about tauopathy, we developed a novel transgenic nematode (Caenorhabditis elegans) model that expresses either wild-type or R406W tau in all the neurons. The wild-type tau-expressing worms exhibited uncoordinated movement (Unc) and neuritic abnormalities. Tau accumulated in abnormal neurites that lost microtubules. Similar abnormalities were found in the worms that expressed low levels of R406W-tau but were not in those expressing comparative levels of wild-type tau. Biochemical studies revealed that tau is aberrantly phosphorylated but forms no detergent-insoluble aggregates. Drug screening performed in these worms identified curcumin, a major phytochemical compound in turmeric, as a compound that reduces not only Unc but also the neuritic abnormalities in both wild-type and R406W tau-expressing worms. Our observations suggest that microtubule stabilization mediates the antitoxicity effect of curcumin. Curcumin is also effective in the worms expressing tau fragment, although it does not prevent the formation of tau-fragment dimers. These data indicate that curcumin improves the tau-induced neuronal dysfunction that is independent of insoluble aggregates of tau.