Tau-mediated iron export prevents ferroptotic damage after ischemic stroke

• Published in: Molecular psychiatry Vol. 22; no. 11; pp. 1520 - 1530
• Main Authors: Tuo, Q-z, Lei, P, Jackman, K A, Li, X-l, Xiong, H, Liuyang, Z-y, Roisman, L, Zhang, S-t, Ayton, S, Wang, Q, Crouch, P J, Ganio, K, Wang, X-c, Pei, L, Adlard, P A, Lu, Y-m, Cappai, R, Wang, J-z, Liu, R, Bush, A I
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2017; Nature Publishing Group
• Subjects: 38/1; 631/337; 631/378; 64/110; 64/60; 82/80; Age; Age Factors; Alzheimer's disease; Amyloid beta-protein; Amyloid precursor protein; Analysis; Animals; Apoptosis; Behavioral Sciences; Biological Psychology; Brain; Brain - metabolism; Brain Injuries - metabolism; Brain Ischemia - metabolism; Care and treatment; Cerebral blood flow; Cerebral circulation; Ceruloplasmin; Damage prevention; Diagnosis; Disease Models, Animal; Ferroptosis; immediate-communication; Infarction, Middle Cerebral Artery - physiopathology; Iron; Iron - metabolism; Ischemia; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Neurons - metabolism; Neurosciences; Neurotoxicity; Occlusion; Oxidative stress; Pharmacotherapy; Psychiatry; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Rodents; Stroke; Stroke - metabolism; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Toxicity
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2017.171

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.