Lithium Treatment Arrests the Development of Neurofibrillary Tangles in Mutant Tau Transgenic Mice with Advanced Neurofibrillary Pathology

Abstract

Neurofibrillary tangles (NFTs) made of phosphorylated tau proteins are a key lesion of Alzheimer's disease and other neurodegenerative diseases, and previous studies have indicated that lithium can decrease tau phosphorylation in tau transgenic models. In this study, we have reassessed the effectiveness of treatment per os with lithium on the prevention, the arrest, or the reversal of NFT development in a tau transgenic line (Tg30tau) developing severe neurofibrillary pathology in the brain and the spinal cord. Wild-type and Tgtau30 mice were treated per os with lithium carbonate or with natrium carbonate by chronic chow feeding for 8 months starting at the age of 3 months (to test for a preventive effect on NFT formation) or by oral gavage for 1 month starting at the age of 9 months (after development of NFTs). In mice treated by oral gavage, a decrease of tau phosphorylation and of Sarkosyl-insoluble aggregated tau was observed in the brain and in the spinal cord. The density of NFTs identified by Gallyas staining in the hippocampus and in the spinal cord was also significantly reduced and was similar to that observed at the beginning of the lithium treatment. In these animals, the level of brain beta-catenin was increased probably as a result of its stabilization by glycogen synthase kinase-3beta inhibition. Despite this inhibitory effect of lithium on NFT development, the motor and working memory deficits were not significantly rescued in these aged animals. Chronic chow feeding with lithium did not alter the development of NFT. Nevertheless, this study indicates that even a relatively short-term per os treatment leading to high blood concentration of lithium is effective in arresting the formation of NFTs in the hippocampus and the spinal cord of a tau transgenic model.

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

“…94 In fact, neuronal deficits have been reported to result from both genetic reduction and specific inhibition of GSK-3, 95,96 highlighting the risk of inhibiting this enzyme. 97 Lithium arrests neuropathology in some AD rodent models, 36,38,39 but these are aggressive models driven by transgene overexpression, where the benefits of lithium inhibiting a dominant pathological target (for example, tau hyperphosphorylation) outweigh lithium-induced neurotoxicity. The lithium-induced neurotoxicity that we and others 17,39 observed might only be detected in normal mice or mice that do not express a neuropathology that is inhibited by lithium.…”

“…31,33,34 Similarly, in transgenic mice that overexpress pathogenic mutant tau, lithium treatment reduced levels of hyperphosphorylation. 35,36,37,38,39 Despite these promising preclinical findings, lithium failed to show therapeutic efficacy for AD in a 10-week multicenter, randomized, single-blind, placebocontrolled trial, with no significant effects on cerebrospinal fluid levels of A and phospho-tau or cognitive end points. 40 Nevertheless, lowering total tau expression is still being explored as a potential treatment for AD, and lithium is still being considered as a treatment option as it lowers both tau protein and mRNA levels in cultured cortical neurons.…”

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

“…In transgenic mouse models of AD, chronic lithium treatment decreased mutant tau protein aggregation (Perez et al, 2003) and arrested the development of neurofibrillary tangles (Leroy et al, 2010). In mouse models of tauopathies, chronic lithium treatment not only inhibited tau phosphorylation and neuronal degeneration mediated by GSK-3 (Noble et al, 2005), but also promoted ubiquitination, thereby decreasing tau-induced lesions (Nakashima et al, 2005).…”

Lithium: the pharmacodynamic actions of the amazing ion

“…GSK3 phosphorylates various proteins, including microtubule-associated proteins (MAPs), such as tau and MAP-1B, which regulate the neuronal cytoskeletal network. Inhibition of GSK3 by lithium [Klein and Melton, 1996;Stambolic et al 1996;ChaleckaFranaszek and Chuang, 1999;De Sarno et al 2002;Beaulieu et al 2004] decreases the phosphorylation of tau protein and of MAP-1B [Hong et al 1997;Munoz-Montano et al 1997;Lovestone et al 1999;Engel et al 2006;Leroy et al 2010], reducing their ability to bind to microtubules, leading to the promotion of microtubule assembly [Hong et al 1997;Munoz-Montano et al 1997] and increased axonal spreading and increases in the growth cone area and perimeter [Garcia-Perez et al 1998], respectively. Thus, lithium-induced GSK3 inhibition can disrupt microtubule assembly, with effects on cytoskeletal protein association dynamics mediating neuroplastic changes [Lenox and Hahn, 2000].…”