4.8 Article

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Journal

MOLECULAR PSYCHIATRY
Volume 22, Issue 3, Pages 396-406

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2016.96

Keywords

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Funding

  1. Australian Research Council
  2. National Health & Medical Research Council (NHMRC) of Australia
  3. Cooperative Research Center for Mental Health
  4. Alzheimer's Australia Dementia Research Foundation
  5. National Natural Science Foundation of China [81571236]
  6. NHMRC Australia Fellowship [AF79]
  7. NHMRC Senior Principal Research Fellowship [1103703, 628386, 1105825]
  8. NHMRC Project Grant [145627]
  9. NHMRC Program Grants [350241, 566529]
  10. NHMRC of Australia
  11. Colonial Foundation
  12. NARSAD
  13. Victorian Government
  14. Operational Infrastructure Support Grant
  15. National Health and Medical Research Council of Australia [1103703] Funding Source: NHMRC

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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 T-2 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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