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.

中文翻译：

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Tau介导的铁输出可预防缺血性中风后的肥大性损害。

tau的功能衰竭会导致年龄依赖性的铁介导的神经毒性，并且随着铁在缺血性中风组织中的积累，我们假设tau衰竭可能会夸大缺血再灌注相关的毒性。确实，单侧短暂性大脑中动脉阻塞（MCAO）抑制了半球tau并增加了年轻（3个月大）小鼠和大鼠的铁水平。野生型小鼠受到铁靶向干预措施的保护：铜蓝蛋白和淀粉样蛋白前体蛋白胞外域，以及铁减少病抑制剂。在这个年龄，tau基因敲除小鼠不表达脑铁，并且可以防止MCAO引起的半球再灌注损伤，这表明tau蛋白的抑制可以预防肥大症。然而，在12个月大的tau基因敲除小鼠中出现的年龄依赖性脑铁加速积累，否定了tau蛋白抑制作用对MCAO诱导的局灶性脑缺血再灌注损伤的保护作用。通过铁靶向干预，tau基因敲除的保护作用在老年小鼠中得以恢复。这些发现引入了铁-铁相互作用，作为铁质增生和缺血性卒中预后的多效调节剂。