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Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Molecular Psychiatry volume 22, pages 396–406 (2017)Cite this article

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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.

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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

  1. Department of Neurology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, China

    P Lei

  2. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia

    P Lei, S Ayton, A T Appukuttan, S Moon, J A Duce, I Volitakis, R Cherny, M Greenough, C Pantelis, D I Finkelstein & A I Bush

  3. Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, West Yorkshire, UK

    J A Duce

  4. Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Parkville, VIC, Australia

    S J Wood & C Pantelis

  5. School of Psychology, University of Birmingham, Birmingham, UK

    S J Wood

  6. ORYGEN Research Centre, University of Melbourne and Melbourne Health, Parkville, VIC, Australia

    G Berger & P McGorry

  7. Department of Child and Adolescent Psychiatry, University of Zürich, Zurich, Switzerland

    G Berger

  8. Department of Electrical and Electronic Engineering, Centre for Neural Engineering, University of Melbourne, Parkville, VIC, Australia

    C Pantelis

  9. Institute of Brain, Behaviour and Mental Health, University of Manchester and Greater Manchester West NHS Mental Health Trust, Manchester, UK

    A Yung

Authors
  1. P Lei
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  2. S Ayton
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  3. A T Appukuttan
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  4. S Moon
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  5. J A Duce
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  6. I Volitakis
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  7. R Cherny
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  8. S J Wood
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  9. M Greenough
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  10. G Berger
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  11. C Pantelis
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  12. P McGorry
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  13. A Yung
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  14. D I Finkelstein
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  15. A I Bush
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Corresponding authors

Correspondence to P Lei or A I Bush.

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.

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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

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  • DOI: https://doi.org/10.1038/mp.2016.96

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