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Intracellular Ion Channel CLIC1: Involvement in Microglia-Mediated β-Amyloid Peptide(1-42) Neurotoxicity

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Abstract

Microglia can exacerbate central nervous system disorders, including stroke and chronic progressive neurodegenerative diseases such as Alzheimer disease. Mounting evidence points to ion channels expressed by microglia as contributing to these neuropathologies. The Chloride Intracellular Channel (CLIC) family represents a class of chloride intracellular channel proteins, most of which are localized to intracellular membranes. CLICs are unusual in that they possess both soluble and integral membrane forms. Amyloid β-peptide (Aβ) accumulation in plaques is a hallmark of familial Alzheimer disease. The truncated Aβ25-35 species was shown previously to increase the expression of CLIC1 chloride conductance in cortical microglia and to provoke microglial neurotoxicity. However, the highly pathogenic and fibrillogenic full-length Aβ1-42 species was not examined, nor was the potential role of CLIC1 in mediating microglial activation and neurotoxicity by other stimuli (e.g. ligands for the Toll-like receptors). In the present study, we utilized a two chamber Transwell™ cell culture system to allow separate treatment of microglia and neurons while examining the effect of pharmacological blockade of CLIC1 in protecting cortical neurons from toxicity caused by Aβ1-42- and lipopolysaccaride-stimulated microglia. Presentation of Aβ1-42 to the upper, microglia-containing chamber resulted in a progressive loss of neurons over 3 days. Neuronal cell injury was prevented by the CLIC1 ion channel blockers IAA-94 [(R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-oxy] acetic acid)] and niflumic acid (2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid) when presented to the upper chamber only. Incubation of microglia with lipopolysaccharide plus interferon-γ led to neuronal cell injury which, however, was insensitive to inhibition by the CLIC1 channel blockers, suggesting a degree of selectivity in agents leading to CLIC1 activation.

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Acknowledgments

L. Facci is the recipient of a fellowship from Fondazione CARIPARO “Progetto Dottorati di Ricerca” Anno 2009.

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  1. Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Largo “E. Meneghetti”, 2, 35131, Padova, Italy

    Stephen D. Skaper, Laura Facci & Pietro Giusti

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Correspondence to Stephen D. Skaper.

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Skaper, S.D., Facci, L. & Giusti, P. Intracellular Ion Channel CLIC1: Involvement in Microglia-Mediated β-Amyloid Peptide(1-42) Neurotoxicity. Neurochem Res 38, 1801–1808 (2013). https://doi.org/10.1007/s11064-013-1084-2

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