title: 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.
authors.affiliation: Laboratory of Histology, Neuroanatomy and Neuropathology, School of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Karelle
authors.initials: K
authors.lastname: Leroy
authors.forename: Kunie
authors.initials: K
authors.lastname: Ando
authors.forename: Céline
authors.initials: C
authors.lastname: Héraud
authors.forename: Zehra
authors.initials: Z
authors.lastname: Yilmaz
authors.forename: Michèle
authors.initials: M
authors.lastname: Authelet
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.forename: Robert
authors.initials: R
authors.lastname: De Decker
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Brion
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D018692:Antimanic Agents / Q000097:blood / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D016651:Lithium Carbonate / Q000097:blood / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000187:drug effects* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012584:Sciatic Nerve / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D018692:Antimanic Agents; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C085349:PHF-1 monoclonal antibody; D016875:tau Proteins; D016651:Lithium Carbonate; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3