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.