Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: Implications of autophagy promotion

• Published in: Neurobiology of disease 2012-04, Vol.46 (1), p.101-108
• Main Authors: Shimada, Kohei, Motoi, Yumiko, Ishiguro, Koichi, Kambe, Taiki, Matsumoto, Shin-ei, Itaya, Masako, Kunichika, Miyuki, Mori, Hideo, Shinohara, Atsuko, Chiba, Momoko, Mizuno, Yoshikuni, Ueno, Takashi, Hattori, Nobutaka
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antimanic Agents - blood; Antimanic Agents - pharmacology; Autophagy; Autophagy - drug effects; GSK-3; Humans; Lithium; Lithium Chloride - blood; Lithium Chloride - pharmacology; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Microtubule-associated protein 1 light chain 3; Motor Skills Disorders - drug therapy; Motor Skills Disorders - etiology; Motor Skills Disorders - pathology; Neurofibrillary tangles; Neurology; Phosphorylation; Tau protein; Tauopathies - complications; Tauopathies - drug therapy; Tauopathies - pathology; Time Factors
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2011.12.050

Abstract Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms including inhibition of glycogen synthase kinase-3 (GSK-3), a major tau kinase. Recently, it has been shown that, in various neurodegenerative proteinopathies, lithium could induce autophagy. To analyze how lithium is therapeutically beneficial in tauopathies, transgenic mice overexpressing human mutant tau (P301L) were treated with oral lithium chloride (LiCl) for 4 months starting at the age of 5 months. At first, we examined the effects of treatment on behavior (using a battery of behavioral tests), tau phosphorylation (by biochemical assays), and number of neurofibrillary tangles (NFTs) (by immunohistopathology). In comparison with control mice, LiCl-treated mice showed a significantly better score in the sensory motor tasks, as well as decreases in tau phosphorylation, soluble tau level, and number of NFTs. Next, we examined lithium effects on autophagy using an antibody against microtubule-associated protein 1 light chain 3 (LC3) as an autophagosome marker. The number of LC3-positive autophagosome-like puncta was increased in neurons of LiCl-treated mice. Neurons containing NFTs were completely LC3-negative, whereas LC3-positive autophagosome-like puncta contained phosphorylated-tau (p-tau). The protein level of p62 was decreased in LiCl-treated mice. These data suggested that oral long-term lithium treatment could attenuate p-tau-induced motor disturbance not only by inhibiting GSK-3 but also by enhancing autophagy in tauopathy model mice.