Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Peng Lei, Scott Ayton, Ambili Appukuttan, Steve Moon, James Duce, Irene Volitakis, Robert Cherny, Stephen Wood, Mark Greenough, Gregor Berger, Christos Pantelis, Patrick D McGorry, Alison R Yung, David Finkelstein, Ashley Bush

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)
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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, which may be related to soluble tau reduction. We found that MRI 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, which traffics amyloid precursor protein to facilitate iron efflux. Thus, tau- and APP- 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 (e.g. Alzheimer’s disease), and may explain lithium-associated motor symptoms in susceptible patients.
Original languageEnglish
Pages (from-to)396-406
JournalMolecular Psychiatry
Volume22
Issue number3
Early online date12 Jul 2016
DOIs
Publication statusPublished - Mar 2017

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