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Tau-mediated iron export prevents ferroptotic damage after ischemic stroke
Q-Z Tuo1,2,3, P Lei2,3, K A Jackman2
1Department of Pathophysiology, Key Laboratory of Ministry of Education for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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.
Insights
Tau protein failure worsens iron-related brain damage after stroke. Suppressing tau protects young mice, but iron buildup in older mice requires iron-targeting treatments to prevent stroke injury.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Functional tau failure is linked to age-dependent, iron-mediated neurotoxicity.
- Iron accumulation in ischemic stroke tissue suggests tau failure may worsen ischemia-reperfusion injury.
Purpose of the Study:
- To investigate the role of tau in exacerbating ischemia-reperfusion injury.
- To explore the interaction between tau and iron in the context of stroke.
- To evaluate the efficacy of iron-targeted interventions and tau suppression in mitigating stroke outcomes.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model in young and aged mice and rats.
- Assessment of tau levels and brain iron content.
- Evaluation of ferroptosis inhibitors and iron-targeted interventions (ceruloplasmin, amyloid precursor protein ectodomain).
- Comparison of wild-type and tau-knockout mouse models.
Main Results:
- MCAO suppressed tau and increased iron in young mice.
- Wild-type mice showed protection with iron-targeted interventions and ferroptosis inhibitors.
- Tau-knockout mice were protected in young age, suggesting tau suppression prevents ferroptosis.
- Age-dependent iron accumulation in 12-month-old tau-knockout mice negated protection.
- Iron-targeting interventions restored protection in aged tau-knockout mice.
Conclusions:
- Tau-iron interaction modulates ferroptosis and ischemic stroke outcomes.
- Tau suppression can be protective against stroke by preventing ferroptosis, but this effect is limited by age-dependent iron accumulation.
- Iron-targeting interventions are crucial for mitigating stroke injury, particularly in the context of tau pathology and aging.
