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Tau-mediated iron export prevents ferroptotic damage after ischemic stroke

Abstract

Functional failure of tau contributes to age-dependent, iron-mediated neurotoxicity, and as iron accumulates in ischemic stroke tissue, we hypothesized that tau failure may exaggerate ischemia–reperfusion-related toxicity. Indeed, unilateral, transient middle cerebral artery occlusion (MCAO) suppressed hemispheric tau and increased iron levels in young (3-month-old) mice and rats. Wild-type mice were protected by iron-targeted interventions: ceruloplasmin and amyloid precursor protein ectodomain, as well as ferroptosis inhibitors. At this age, tau-knockout mice did not express elevated brain iron and were protected against hemispheric reperfusion injury following MCAO, indicating that tau suppression may prevent ferroptosis. However, the accelerated age-dependent brain iron accumulation that occurs in tau-knockout mice at 12 months of age negated the protective benefit of tau suppression against MCAO-induced focal cerebral ischemia–reperfusion injury. The protective benefit of tau knockout was revived in older mice by iron-targeting interventions. These findings introduce tau–iron interaction as a pleiotropic modulator of ferroptosis and ischemic stroke outcome.

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Acknowledgements

We thank Drs Mian Bi, Lars Ittner and Brian Stevens for technical assistance, and Drs Geoffrey Donnan, David Howells and Craig Rosenfeld for critical review of the manuscript. This work was supported by funds from the Australian Research Council, the National Health and Medical Research Council of Australia (NHMRC), the Cooperative Research Center for Mental Health, Alzheimer’s Australia Dementia Research Foundation, National Natural Science Foundation of China (81722016, 81571236, 81271403, 81471304, 91632115) and the Fundamental Research Funds for the Central Universities (2015XJGH013, 2017SCU12042). P Lei is supported by the Recruitment Program of Global Young Experts of China.

Author contributions

PL and AIB conceived and raised funds for the study. RL raised funds for the study. Q-zT, PL, KAJ, X-lL, Z-yL, LR, SA, QW, PJC, PAA, RL and AIB designed and performed the experiments. KG and LP assisted with the experiments. PL, X-cW, Y-mL, RC, J-zW, RL and AIB supervised the experiments. Q-zT, PL and AIB integrated the data and wrote the drafts of the manuscript. All authors edited the manuscript.

NOTES ADDED IN PROOF

Since the acceptance of this work, we learned that the protection of 3 month-old tau knockout mice from brain damage after MCAO with reperfusion recapitulated parallel independent findings using a different tau knockout strain, to be through suppressing excitotoxic cell death (Bi et al, Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nature Communications, accepted, NCOMMS-17-18086).

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Correspondence to P Lei, R Liu or A I Bush.

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Dr Adlard is a shareholder in and paid scientific consultant for Prana Biotechnology Ltd. Dr Bush is a shareholder in Prana Biotechnology Ltd, Cogstate Ltd, Mesoblast Ltd, NextVet Ltd, Brighton Biotech LLC and Cogstate Ltd, and a consultant for Collaborative Medicinal Development Pty Ltd.

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Tuo, Qz., Lei, P., Jackman, K. et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry 22, 1520–1530 (2017). https://doi.org/10.1038/mp.2017.171

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