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

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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.

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Acknowledgements

We thank Dr. P. Davies for PHF1 antibody. We also thank S. Fujisawa, M. Onbe, T. Kanamori and R. Wada for technical assistance. This work was supported by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (T.I.), Taisho Pharmaceutical Co., Ltd. (T.I.), the Zikei Institute of Psychiatry (T.I., H.N.), the National Institutes of Health (V.M.-Y.L., J.Q.T.), as well as by grants from the Marian S. Ware Alzheimer Program (V.M.-Y.L., J.Q.T.).

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Authors and Affiliations

  1. Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-Cho, 700-8558, Okayama, Japan

    Hanae Nakashima, Takeshi Ishihara, Pilar Suguimoto, Osamu Yokota, Etsuko Oshima, Aki Kugo, Seishi Terada, Takashi Hamamura & Shigetoshi Kuroda

  2. The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and Institute on Aging, The University of Pennsylvania School of Medicine, 3600 Spruce Street, Philadelphia, PA, 19104-4283, USA

    John Q. Trojanowski & Virginia M.-Y. Lee

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  1. Hanae Nakashima
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  2. Takeshi Ishihara
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Correspondence to Takeshi Ishihara.

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Nakashima, H., Ishihara, T., Suguimoto, P. et al. Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol 110, 547–556 (2005). https://doi.org/10.1007/s00401-005-1087-4

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  • DOI: https://doi.org/10.1007/s00401-005-1087-4

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