PubMed 18987185

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: ClIC1 , Slo1

Title: CLIC1 function is required for beta-amyloid-induced generation of reactive oxygen species by microglia.

Authors: Rosemary H Milton, Rosella Abeti, Stefania Averaimo, Silvia DeBiasi, Laura Vitellaro, Lele Jiang, Paul M G Curmi, Samuel N Breit, Michael R Duchen, Michele Mazzanti

Journal, date & volume: J. Neurosci., 2008 Nov 5 , 28, 11488-99

PubMed link:

The Alzheimer's disease (AD) brain is characterized by plaques containing beta-amyloid (Abeta) protein surrounded by astrocytes and reactive microglia. Activation of microglia by Abeta 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 Abeta upregulates a chloride current mediated by the chloride intracellular channel 1 (CLIC1) protein in microglia. We now demonstrate that Abeta promotes the acute translocation of CLIC1 from the cytosol to the plasma membrane of microglia, where it mediates a chloride conductance. Both the Abeta 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 Abeta-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.