Journal
MOLECULAR PSYCHIATRY
Volume 22, Issue 11, Pages 1520-1530Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2017.171
Keywords
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Funding
- Australian Research Council
- National Health and Medical Research Council of Australia (NHMRC)
- Cooperative Research Center for Mental Health
- Alzheimer's Australia Dementia Research Foundation
- National Natural Science Foundation of China [81722016, 81571236, 81271403, 81471304, 91632115]
- Fundamental Research Funds for the Central Universities [2015XJGH013, 2017SCU12042]
- Recruitment Program of Global Young Experts of China
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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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