Abstract
Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T2 relaxation time changes in subjects commenced on lithium therapy were consistent with iron elevation. In mice, lithium treatment lowers brain tau levels and increases nigral and cortical iron elevation that is closely associated with neurodegeneration, cognitive loss and parkinsonian features. In neuronal cultures lithium attenuates iron efflux by lowering tau protein that traffics amyloid precursor protein to facilitate iron efflux. Thus, tau- and amyloid protein precursor-knockout mice were protected against lithium-induced iron elevation and neurotoxicity. These findings challenge the appropriateness of lithium as a potential treatment for disorders where brain iron is elevated (for example, Alzheimer’s disease), and may explain lithium-associated motor symptoms in susceptible patients.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cade JF . Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2: 349–352.
Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010; 375: 385–395.
Phiel CJ, Klein PS . Molecular targets of lithium action. Annu Rev Pharmacol Toxicol 2001; 41: 789–813.
Grof P, Müller-Oerlinghausen B . A critical appraisal of lithium's efficacy and effectiveness: the last 60 years. Bipolar Disord 2009; 11 (Suppl 2): 10–19.
Lei P, Ayton S, Bush AI, Adlard PA . GSK-3 in neurodegenerative diseases. Int J Alzheimers Dis 2011; 2011: 189246.
Ghadirian AM, Annable L, Bélanger MC, Chouinard G . A cross-sectional study of parkinsonism and tardive dyskinesia in lithium-treated affective disordered patients. J Clin Psychiatry 1996; 57: 22–28.
Dallocchio C, Mazzarello P . A case of Parkinsonism due to lithium intoxication: treatment with Pramipexole. J Clin Neurosci 2002; 9: 310–311.
Shopsin B, Gershon S . Cogwheel rigidity related to lithium maintenance. Am J Psychiatry 1975; 132: 536–538.
Reches A, Tietler J, Lavy S . Parkinsonism due to lithium carbonate poisoning. Arch Neurol 1981; 38: 471.
Apte SN, Langston JW . Permanent neurological deficits due to lithium toxicity. Ann Neurol 1983; 13: 453–455.
Lang AE . Lithium and parkinsonism. Ann Neurol 1984; 15: 214.
Muthane UB, Prasad BN, Vasanth A, Satishchandra P . Tardive Parkinsonism, orofacial dyskinesia and akathisia following brief exposure to lithium carbonate. J Neurol Sci 2000; 176: 78–79.
Mazzini L, Oggioni GD, Nasuelli N, Servo S, Testa L, Monaco F . Disabling Parkinsonism following brief exposure to lithium carbonate in amyotrophic lateral sclerosis. J Neurol 2011; 258: 333–334.
Fallgatter AJ, Strik WK . Reversible neuropsychiatric side effects of lithium with normal serum levels. A case report. Nervenarzt 1997; 68: 586–590.
Perenyi A, Rihmer Z, Banki CM . Parkinsonian symptoms with lithium, lithium-neuroleptic, and lithium-antidepressant treatment. J Affect Disord 1983; 5: 171–177.
Marras C, Herrmann N, Fischer HD, Fung K, Gruneir A, Rochon PA et al. Lithium use in older adults is associated with increased prescribing of parkinson medications. Am J Geriatr Psychiatry 2016; 24: 301–309.
Gómez-Sintes R, Lucas JJ . NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy. J Clin Invest 2010; 120: 2432–2445.
Taliyan R, Ramagiri S . Delayed neuroprotection against cerebral ischemia reperfusion injury: putative role of BDNF and GSK-3beta. J Recept Signal Transduct Res 2015; 36: 1–9.
Berger GE, Wood SJ, Ross M, Hamer CA, Wellard RM, Pell G et al. Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study. Curr Pharm Des 2012; 18: 570–575.
Yung AR, Phillips LJ, Yuen HP, McGorry PD . Risk factors for psychosis in an ultra high-risk group: psychopathology and clinical features. Schizophr Res 2004; 67: 131–142.
Benarous X, Consoli A, Milhiet V, Cohen D . Early interventions for youths at high risk for bipolar disorder: a developmental approach. Eur Child Adolesc Psychiatry 2016; 25: 217–233.
Berger GE, Wood S, McGorry PD . Incipient neurovulnerability and neuroprotection in early psychosis. Psychopharmacol Bull 2003; 37: 79–101.
van Rooden S, Versluis MJ, Liem MK, Milles J, Maier AB, Oleksik AM et al. Cortical phase changes in Alzheimer's disease at 7T MRI: a novel imaging marker. Alzheimers Dement 2014; 10: e19–e26.
Hong M, Chen DC, Klein PS, Lee VM . Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem 1997; 272: 25326–25332.
Munoz-Montano JR, Moreno FJ, Avila J, Diaz-Nido J . Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons. FEBS Lett 1997; 411: 183–188.
Lovestone S, Davis DR, Webster MT, Kaech S, Brion J-P, Matus A et al. Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations. Biol Psychiatry 1999; 45: 995–1003.
Takahashi M, Yasutake K, Tomizawa K . Lithium inhibits neurite growth and tau protein kinase I/glycogen synthase kinase-3beta-dependent phosphorylation of juvenile tau in cultured hippocampal neurons. J Neurochem 1999; 73: 2073–2083.
Sun X, Sato S, Murayama O, Murayama M, Park JM, Yamaguchi H et al. Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci Lett 2002; 321: 61–64.
Phiel CJ, Wilson CA, Lee VM-Y, Klein PS . GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature 2003; 423: 435–439.
Su Y, Ryder J, Li B, Wu X, Fox N, Solenberg P et al. Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Biochemistry 2004; 43: 6899–6908.
Rockenstein E, Torrance M, Adame A, Mante M, Bar-on P, Rose JB et al. Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci 2007; 27: 1981–1991.
Sofola O, Kerr F, Rogers I, Killick R, Augustin H, Gandy C et al. Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease. PLoS Genet 2010; 6: e1001087.
Toledo EM, Inestrosa NC . Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease. Mol Psychiatry 2010; 15: 272–285, 228.
Fiorentini A, Rosi MC, Grossi C, Luccarini I, Casamenti F . Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice. PLoS One 2010; 5: e14382.
Pérez M, Hernández F, Lim F, Díaz-Nido J, Avila J . Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J Alzheimers Dis 2003; 5: 301–308.
Nakashima H, Ishihara T, Suguimoto P, Yokota O, Oshima E, Kugo A et al. Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol 2005; 110: 547–556.
Noble WJ, Planel E, Zehr C, Olm V, Meyerson J, Suleman F et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 2005; 102: 6990–6995.
Engel T, Goñi-Oliver P, Lucas JJ, Avila J, Hernández F . Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J Neurochem 2006; 99: 1445–1455.
Leroy K, Ando K, Héraud C, Yilmaz Z, Authelet M, Boeynaems J-M et al. Lithium treatment arrests the development of neurofibrillary tangles in mutant tau transgenic mice with advanced neurofibrillary pathology. J Alzheimers Dis 2010; 19: 705–719.
Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A et al. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry 2009; 70: 922–931.
Rametti A, Esclaire F, Yardin C, Cogné N, Terro F . Lithium down-regulates tau in cultured cortical neurons: a possible mechanism of neuroprotection. Neurosci Lett 2008; 434: 93–98.
Martin L, Magnaudeix A, Esclaire F, Yardin C, Terro F . Inhibition of glycogen synthase kinase-3beta downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A. Brain Res 2009; 1252: 66–75.
Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 2012; 18: 291–295.
Lei P, Ayton S, Moon S, Zhang Q, Volitakis I, Finkelstein DI et al. Motor and cognitive deficits in aged tau knockout mice in two background strains. Mol Neurodegener 2014; 9: 29.
Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ, Alaverdyan M et al. Loss of MAP function leads to hippocampal synapse loss and deficits in the Morris water maze with aging. J Neurosci 2014; 34: 7124–7136.
Zhukareva V, Vogelsberg-Ragaglia V, Van Deerlin VM, Bruce J, Shuck T, Grossman M et al. Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia. Ann Neurol 2001; 49: 165–175.
Zhukareva V, Sundarraj S, Mann D, Sjogren M, Blenow K, Clark CM et al. Selective reduction of soluble tau proteins in sporadic and familial frontotemporal dementias: an international follow-up study. Acta Neuropathol 2003; 105: 469–476.
Ksiezak-Reding H, Binder LI, Yen S-HC . Immunochemical and biochemical characterization of tau proteins in normal and Alzheimer's disease brains with Alz 50 and Tau-1. J Biol Chem 1988; 263: 7948–7953.
Shin RW, Iwaki T, Kitamoto T, Sato Y, Tateishi J . Massive accumulation of modified tau and severe depletion of normal tau characterize the cerebral cortex and white matter of Alzheimer's disease. Demonstration using the hydrated autoclaving method. Am J Pathol 1992; 140: 937–945.
Khatoon S, Grundke-Iqbal I, Iqbal K . Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Lett 1994; 351: 80–84.
van Eersel J, Bi M, Ke YD, Hodges JR, Xuereb JH, Gregory GC et al. Phosphorylation of soluble tau differs in Pick's disease and Alzheimer's disease brains. J Neural Transm 2009; 116: 1243–1251.
Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K et al. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 2010; 142: 857–867.
McCarthy RC, Park YH, Kosman DJ . sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin. EMBO Rep 2014; 15: 809–815.
Wong BX, Tsatsanis A, Lim LQ, Adlard PA, Bush AI, Duce JA . beta-Amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin. PLoS One 2014; 9: e114174.
Ayton S, Lei P . Nigral iron elevation is an invariable feature of Parkinson's disease and is a sufficient cause of neurodegeneration. Biomed Res Int 2014; 2014: 581256.
Campbell WG, Raskind MA, Gordon T, Shaw CM . Iron pigment in the brain of a man with tardive dyskinesia. Am J Psychiatry 1985; 142: 364–365.
Yung AR, Yuen HP, McGorry PD, Phillips LJ, Kelly D, Dell'Olio M et al. Mapping the onset of psychosis: the Comprehensive Assessment of At-Risk Mental States. Aust N Z J Psychiatry 2005; 39: 964–971.
Yung AR, Phillips LJ, Yuen HP, Francey SM, McFarlane CA, Hallgren M et al. Psychosis prediction: 12-month follow up of a high-risk ("prodromal") group. Schizophr Res 2003; 60: 21–32.
Greenough MA, Volitaskis I, Li Q-X, Laughton KM, Evin G, Ho M et al. Presenilins promote the cellular uptake of copper and zinc and maintain copper chaperone of SOD1-dependent copper/zinc superoxide dismutase activity. J Biol Chem 2011; 286: 9776–9786.
Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP . Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci 2001; 114 (Pt 6): 1179–1187.
Chen JC, Hardy PA, Clauberg M, Joshi JG, Parravano J, Deck JH et al. T2 values in the human brain: comparison with quantitative assays of iron and ferritin. Radiology 1989; 173: 521–526.
Bartzokis G, Garber HJ, Marder SR, Olendorf WH . MRI in tardive dyskinesia: shortened left caudate T2. Biol Psychiatry 1990; 28: 1027–1036.
Dhenain M, Duyckaerts C, Michot JL, Volk A, Picq JL, Boller F . Cerebral T2-weighted signal decrease during aging in the mouse lemur primate reflects iron accumulation. Neurobiol Aging 1998; 19: 65–69.
Positano V, Salani B, Pepe A, Santarelli MF, De Marchi D, Ramazzotti A et al. Improved T2* assessment in liver iron overload by magnetic resonance imaging. Magn Reson Imaging 2009; 27: 188–197.
Sun H, Walsh AJ, Lebel RM, Blevins G, Catz I, Lu JQ et al. Validation of quantitative susceptibility mapping with Perls' iron staining for subcortical gray matter. Neuroimage 2014; 105: 486–492.
Caccamo A, Oddo S, Tran LX, LaFerla FM . Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol 2007; 170: 1669–1675.
Malhi GS, Adams D, Berk M . Is lithium in a class of its own? A brief profile of its clinical use. Aust NZ J Psychiatry 2009; 43: 1096–1104.
Frank GB, Jhamandas K . Effects of drugs acting alone and in combination on the motor activity of intact mice. Br J Pharmacol 1970; 39: 696–706.
Healy TE, Lautch H, Hall N, Tomlin PJ, Vickers MD . Interdisciplinary study of diazepam sedation for outpatient dentistry. Br Med J 1970; 3: 13–17.
Tornberg J, Segerstråle M, Kulesskaya N, Voikar V, Taira T, Airaksinen MS . KCC2-deficient mice show reduced sensitivity to diazepam, but normal alcohol-induced motor impairment, gaboxadol-induced sedation, and neurosteroid-induced hypnosis. Neuropsychopharmacology 2007; 32: 911–918.
Zeller A, Crestani F, Camenisch I, Iwasato T, Itohara S, Fritschy JM et al. Cortical glutamatergic neurons mediate the motor sedative action of diazepam. Mol Pharmacol 2008; 73: 282–291.
Snyder SH, Taylor KM, Coyle JT, Meyerhoff JL . The role of brain dopamine in behavioral regulation and the actions of psychotropic drugs. Am J Psychiatry 1970; 127: 199–207.
Cox C, Harrison-Read PE, Steinberg H, Tomkiewicz M . Lithium attenuates drug-induced hyperactivity in rats. Nature 1971; 232: 336–338.
Friedman ES, Gershon S . Effect of lithium on brain dopamine. Nature 1973; 243: 520–521.
Dziedzicka-Wasylewska M, Maćkowiak M, Fijat K, Wedzony K . Adaptive changes in the rat dopaminergic transmission following repeated lithium administration. J Neural Transm 1996; 103: 765–776.
Atack JR, Cook SM, Watt AP, Fletcher SR, Ragan CI . In vitro and in vivo inhibition of inositol monophosphatase by the bisphosphonate L-690,330. J Neurochem 1993; 60: 652–658.
Meijer L, Skaltsounis AL, Magiatis P, Polychronopoulos P, Knockaert M, Leost M et al. GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chem Biol 2003; 10: 1255–1266.
Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJ, Hopkins R, Smith DW et al. beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 1995; 81: 525–531.
Dallman PR, Spirito RA . Brain iron in the rat: extremely slow turnover in normal rats may explain long-lasting effects of early iron deficiency. J Nutr 1977; 107: 1075–1081.
Chen JH, Shahnavas S, Singh N, Ong WY, Walczyk T . Stable iron isotope tracing reveals significant brain iron uptake in adult rats. Metallomics 2013; 5: 167–173.
Murray N, Hopwood S, Balfour DJ, Ogston S, Hewick DS . The influence of age on lithium efficacy and side-effects in out-patients. Psychol Med 1983; 13: 53–60.
Bell AJ, Cole A, Eccleston D, Ferrier IN . Lithium neurotoxicity at normal therapeutic levels. Br J Psychiatry 1993; 162: 689–692.
Flint A . Ageing as a risk factor for lithium neurotoxicity at therapeutic serum levels. Br J Psychiatry 1993; 163: 555–556.
Hare D, Ayton S, Bush A, Lei P . A delicate balance: iron metabolism and diseases of the brain. Front Aging Neurosci 2013; 5: 34.
Hajek T, Kopecek M, Hoschl C, Alda M . Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis. J Psychiatry Neurosci 2012; 37: 333–343.
Pfennig A, Alda M, Young T, MacQueen G, Rybakowski J, Suwalska A et al. Prophylactic lithium treatment and cognitive performance in patients with a long history of bipolar illness: no simple answers in complex disease-treatment interplay. Int J Bipolar Disord 2014; 2: 1.
Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ . Effects of lithium on cognitive performance: a meta-analysis. J Clin Psychiatry 2009; 70: 1588–1597.
Mora E, Portella MJ, Forcada I, Vieta E, Mur M . Persistence of cognitive impairment and its negative impact on psychosocial functioning in lithium-treated, euthymic bipolar patients: a 6-year follow-up study. Psychol Med 2013; 43: 1187–1196.
Evrensel A, Unsalver BO, Ceylan ME, Comert G . Lithium-induced cortical atrophy and cognitive dysfunction. BMJ Case Rep 2014; 2014: pii: bcr2014207646.
Wang X, Culotta VC, Klee CB . Superoxide dismutase protects calcineurin from inactivation. Nature 1996; 383: 434–437.
Namgaladze D, Hofer HW, Ullrich V . Redox control of calcineurin by targeting the binuclear Fe(2+)-Zn(2+) center at the enzyme active site. J Biol Chem 2002; 277: 5962–5969.
Huang C, Li J, Zhang Q, Huang X . Role of bioavailable iron in coal dust-induced activation of activator protein-1 and nuclear factor of activated T cells: difference between Pennsylvania and Utah coal dusts. Am J Respir Cell Mol Biol 2002; 27: 568–574.
Huang X, Dai J, Huang C, Zhang Q, Bhanot O, Pelle E . Deferoxamine synergistically enhances iron-mediated AP-1 activation: a showcase of the interplay between extracellular-signal-regulated kinase and tyrosine phosphatase. Free Radic Res 2007; 41: 1135–1142.
Kremer A . GSK3 and Alzheimer’s disease: facts and fiction. Front Mol Neurosci 2011; 4: 1–10.
Hu S, Begum AN, Jones MR, Oh MS, Beech WK, Beech BH et al. GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals. Neurobiol Dis 2009; 33: 193–206.
Gómez-Sintes R, Hernández F, Bortolozzi A, Artigas F, Avila J, Zaratin P et al. Neuronal apoptosis and reversible motor deficit in dominant-negative GSK-3 conditional transgenic mice. EMBO J 2007; 26: 2743–2754.
Ayton S, Lei P . The Abeta-induced NFAT apoptotic pathway is also activated by GSK-3 inhibition: implications for Alzheimer therapeutics. J Neurosci 2012; 32: 9454–9456.
Macdonald A, Briggs K, Poppe M, Higgins A, Velayudhan L, Lovestone S . A feasibility and tolerability study of lithium in Alzheimer's disease. Int J Geriatr Psychiatry 2008; 23: 704–711.
Aggarwal SP, Zinman L, Simpson E, Mckinley J, Jackson KE, Pinto H et al. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010; 9: 481–488.
Swash M . Lithium time-to-event trial in amyotrophic lateral sclerosis stops early for futility. Lancet Neurol 2010; 9: 449–451.
Verstraete E, Veldink JH, Huisman MH, Draak T, Uijtendaal EV, van der Kooi AJ et al. Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial. J Neurol Neurosurg Psychiatry 2012; 83: 557–564.
Ayton S, Lei P, Bush AI . Biometals and their therapeutic implications in Alzheimer's disease. Neurotherapeutics 2014; 12: 109–120.
Langkammer C, Enzinger C, Quasthoff S, Grafenauer P, Soellinger M, Fazekas F et al. Mapping of iron deposition in conjunction with assessment of nerve fiber tract integrity in amyotrophic lateral sclerosis. J Magn Reson Imaging 2010; 31: 1339–1345.
Oba H, Araki T, Ohtomo K, Monzawa S, Uchiyama G, Koizumi K et al. Amyotrophic lateral sclerosis: T2 shortening in motor cortex at MR imaging. Radiology 1993; 189: 843–846.
Acknowledgements
We thank A Sedjahtera, L Lam, L Gunawan, L Bray and K Wikhe for technical assistance. We also acknowledge L Phillips and B Nelson for their contributions in lithium human trial. This study was supported by funds from the Australian Research Council, the National Health & Medical Research Council (NHMRC) of Australia, the Cooperative Research Center for Mental Health, Alzheimer’s Australia Dementia Research Foundation and National Natural Science Foundation of China (81571236). A Bush was supported by a NHMRC Australia Fellowship (AF79) and a NHMRC Senior Principal Research Fellowship (1103703). C Pantelis was supported by a NHMRC Senior Principal Research Fellowship (628386 and 1105825). The imaging work on lithium was supported by NHMRC Project Grant (145627) and NHMRC Program Grants (350241 and 566529). P McGorry currently receives research support from NHMRC of Australia, the Colonial Foundation and NARSAD. Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant.
Author contributions
PL and AIB conceived and raised funds for the study. PL, SA, JAD, RC, DIF and AIB designed and performed the experiments. ATA, SM, IV and MG and assisted with the experiments. SJW, GB, CP, PM and AY conducted the lithium human trial. PL and AIB integrated the data and wrote the drafts of the manuscript. All authors edited the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
Dr Finkelstein is a paid scientific consultant for Prana Biotechnology. Dr Bush is a shareholder in Prana Biotechnology, Eucalyptus, Mesoblast, Brighton Biotech and Nextvet, and a paid consultant for Collaborative Medicinal Developments. Dr Pantelis has participated on Advisory Boards for Janssen-Cilag, Astra-Zeneca, Lundbeck and Servier. He has received honoraria for talks presented at educational meetings organized by Astra-Zeneca, Janssen-Cilag, Eli Lilly, Pfizer, Lundbeck and Shire. Dr McGorry receives unrestricted research funding from Astra-Zenica, Eli Lilly, Janssen-Cilag, Pfizer and Novartis, as well as honoraria for educational activities with Astra-Zenica, Eli Lilly, Janssen-Cilag, Pfizer, Bristol Myer Squibb, Roche and the Lunbeck Institute. The remaining authors declare no conflicts of interest.
Additional information
Supplementary Information accompanies the paper on the Molecular Psychiatry website
Supplementary information
Rights and permissions
About this article
Cite this article
Lei, P., Ayton, S., Appukuttan, A. et al. Lithium suppression of tau induces brain iron accumulation and neurodegeneration. Mol Psychiatry 22, 396–406 (2017). https://doi.org/10.1038/mp.2016.96
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2016.96
This article is cited by
-
Friend or foe: role of pathological tau in neuronal death
Molecular Psychiatry (2023)
-
Perturbed iron biology in the prefrontal cortex of people with schizophrenia
Molecular Psychiatry (2023)
-
Alzheimer’s Disease: Novel Targets and Investigational Drugs for Disease Modification
Drugs (2023)
-
Tau suppresses microtubule-regulated pancreatic insulin secretion
Molecular Psychiatry (2023)
-
Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential
Translational Neurodegeneration (2022)