title: Lithium suppression of tau induces brain iron accumulation and neurodegeneration.
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 T2relaxation 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.
authors.affiliation: Department of Neurology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, China.|Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: P
authors.identifier: 0000-0001-5652-1962
authors.initials: P
authors.lastname: Lei
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Ayton
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: A T
authors.initials: AT
authors.lastname: Appukuttan
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Moon
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.|Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, West Yorkshire, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Duce
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Volitakis
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Cherny
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Parkville, VIC, Australia.|School of Psychology, University of Birmingham, Birmingham, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Wood
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Greenough
authors.affiliation: ORYGEN Research Centre, University of Melbourne and Melbourne Health, Parkville, VIC, Australia.|Department of Child and Adolescent Psychiatry, University of Zürich, Zurich, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Berger
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.|Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Parkville, VIC, Australia.|Centre for Neural Engineering, Department of Electrical and Electronic Engineering, University of Melbourne, Parkville, VIC, Australia.
authors.forename: C
authors.identifier: 0000-0002-9565-0238
authors.initials: C
authors.lastname: Pantelis
authors.affiliation: ORYGEN Research Centre, University of Melbourne and Melbourne Health, Parkville, VIC, Australia.
authors.forename: P
authors.initials: P
authors.lastname: McGorry
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester and Greater Manchester West NHS Mental Health Trust, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Yung
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: D I
authors.initials: DI
authors.lastname: Finkelstein
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: A I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D008094:Lithium / Q000009:adverse effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000378:metabolism; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D008094:Lithium; D007501:Iron