Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies

Hanae Nakashima, Takeshi Ishihara, Pilar Suguimoto, Osamu Yokota, Etsuko Oshima, Aki Kugo, Seishi Terada, Takashi Hamamura, John Q. Trojanowski, Virginia M.Y. Lee, Shigetoshi Kuroda

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Abstract

Lithium, a widely used drug for treating affective disorders, is known to inhibit glycogen synthase kinase-3 (GSK-3), which is one of the major tau kinases. Thus, lithium could have therapeutic benefit in neurodegenerative tauopathies by reducing tau hyperphosphorylation. We tested this hypothesis and showed that long-term administration of lithium at relatively low therapeutic concentrations to transgenic mice that recapitulate Alzheimer's disease (AD)-like tau pathologies reduces tau lesions, primarily by promoting their ubiquitination rather than by inhibiting tau phosphorylation. These findings suggest novel mechanisms whereby lithium treatment could ameliorate tauopathies including AD. Because lithium also has been shown to reduce the burden of amyloid-β pathologies, it is plausible that lithium could reduce the formation of both amyloid plaques and tau tangles, the two pathological hallmarks of AD, and thereby ameliorate the behavioral deficits in AD.

Original languageEnglish
Pages (from-to)547-556
Number of pages10
JournalActa neuropathologica
Volume110
Issue number6
DOIs
Publication statusPublished - Dec 1 2005

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Keywords

  • Animal models
  • GSK-3
  • Lithium
  • Tau
  • Ubiquitination

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Nakashima, H., Ishihara, T., Suguimoto, P., Yokota, O., Oshima, E., Kugo, A., Terada, S., Hamamura, T., Trojanowski, J. Q., Lee, V. M. Y., & Kuroda, S. (2005). Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta neuropathologica, 110(6), 547-556. https://doi.org/10.1007/s00401-005-1087-4