Pharmacology and Therapeutics - Research Publications

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Author: Adlard, Paul × Author: Ayton, Scott × Author: Bush, Ashley × Type: Journal Article ×

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    Tau-mediated iron export prevents ferroptotic damage after ischemic stroke
    Tuo, Q-Z ; Lei, P ; Jackman, KA ; Li, X-I ; Xiong, H ; Li, X-L ; Liuyang, Z-Y ; Roisman, L ; Zhang, S-T ; Ayton, S ; Wang, Q ; Crouch, PJ ; Ganio, K ; Wang, X-C ; Pei, L ; Adlard, PA ; Lu, Y-M ; Cappai, R ; Wang, J-Z ; Liu, R ; Bush, AI (NATURE PUBLISHING GROUP, 2017-11)
    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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    A comparison of ceruloplasmin to biological polyanions in promoting the oxidation of Fe2+ under physiologically relevant conditions
    Wong, BX ; Ayton, S ; Lam, LQ ; Lei, P ; Adlard, PA ; Bush, AI ; Duce, JA (ELSEVIER SCIENCE BV, 2014-12)
    BACKGROUND: Iron oxidation is thought to be predominantly handled enzymatically in the body, to minimize spontaneous combustion with oxygen and to facilitate cellular iron export by loading transferrin. This process may be impaired in disease, and requires more accurate analytical assays to interrogate enzymatic- and auto-oxidation within a physiologically relevant environment. METHOD: A new triplex ferroxidase activity assay has been developed that overcomes the previous assay limitations of measuring iron oxidation at a physiologically relevant pH and salinity. RESULTS: Revised enzymatic kinetics for ceruloplasmin (Vmax≈35μMFe(3+)/min/μM; Km≈15μM) are provided under physiological conditions, and inhibition by sodium azide (Ki for Ferric Gain 78.3μM, Ki for transferrin loading 8.1×10(4)μM) is quantified. We also used this assay to characterize the non-enzymatic oxidation of iron that proceeded linearly under physiological conditions. CONCLUSIONS AND GENERAL SIGNIFICANCE: These findings indicate that the requirement of an enzyme to oxidize iron may only be necessary under conditions of adverse pH or anionic strength, for example from hypoxia. In a normal physiological environment, Fe(3+) incorporation into transferrin would be sufficiently enabled by the biological polyanions that are prevalent within extracellular fluids.