Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies |
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Authors: | 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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Affiliation: | (1) Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-Cho, 700-8558 Okayama, Japan;(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 |
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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 Alzheimers 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- 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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Keywords: | Tau Animal models Lithium GSK-3 Ubiquitination |
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