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The Journal of Neuroscience, November 5, 2008, 28(45):11488-11499; doi:10.1523/JNEUROSCI.2431-08.2008

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Neurobiology of Disease
CLIC1 Function Is Required for β-Amyloid-Induced Generation of Reactive Oxygen Species by Microglia

Rosemary H. Milton,¹ Rosella Abeti,¹ Stefania Averaimo,² Silvia DeBiasi,² Laura Vitellaro,² Lele Jiang,^3,4 Paul M. G. Curmi,⁴ Samuel N. Breit,^3,4 Michael R. Duchen,¹ and Michele Mazzanti²

¹Department of Physiology, University College London, London WC1E 6BT, United Kingdom, ²Department of Biomolecular Sciences and Biotechnology, University of Milan, I-20133 Milan, Italy, ³Centre for Immunology, St. Vincent's Hospital, Sydney 2010, Australia, and ⁴School of Physics, University of New South Wales, Sydney 2052, Australia

Correspondence should be addressed to Dr. Michele Mazzanti, Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Via Celoria 26, I-20133 Milan, Italy. Email: michele.mazzanti{at}unimi.it

The Alzheimer's disease (AD) brain is characterized by plaques containing β-amyloid (Aβ) protein surrounded by astrocytes and reactive microglia. Activation of microglia by Aβ initiates production of reactive oxygen species (ROS) by the plasmalemmal NADPH oxidase; the resultant oxidative stress is thought to contribute to neurodegeneration in AD. We have previously shown that Aβ upregulates a chloride current mediated by the chloride intracellular channel 1 (CLIC1) protein in microglia. We now demonstrate that Aβ promotes the acute translocation of CLIC1 from the cytosol to the plasma membrane of microglia, where it mediates a chloride conductance. Both the Aβ induced Cl^– conductance and ROS generation were prevented by pharmacological inhibition of CLIC1, by replacement of chloride with impermeant anions, by an anti-CLIC1 antibody and by suppression of CLIC1 expression using siRNA. Thus, the CLIC1-mediated Cl^– conductance is required for Aβ-induced generation of neurotoxic ROS by microglia. Remarkably, CLIC1 activation is itself dependent on oxidation by ROS derived from the activated NADPH oxidase. We therefore propose that CLIC1 translocation from the cytosol to the plasma membrane, in response to redox modulation by NADPH oxidase-derived ROS, provides a feedforward mechanism that facilitates sustained microglial ROS generation by the NAPDH oxidase.

Key words: microglia; β-amyloid; ROS; CLIC1; NADPH oxidase; neurodegeneration

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Received May 29, 2008; revised July 21, 2008; accepted Aug. 30, 2008.

Correspondence should be addressed to Dr. Michele Mazzanti, Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Via Celoria 26, I-20133 Milan, Italy. Email: michele.mazzanti{at}unimi.it

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