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The Journal of Neuroscience, June 9, 2004, 24(23):5322-5330; doi:10.1523/JNEUROSCI.1170-04.2004

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Cellular/Molecular
Involvement of the Intracellular Ion Channel CLIC1 in Microglia-Mediated -Amyloid-Induced Neurotoxicity

Gaia Novarino,^1 * Cinzia Fabrizi,^2 * Raffaella Tonini,^1 * Michela A. Denti,³ Fiorella Malchiodi-Albedi,⁵ Giuliana M. Lauro,⁴ Benedetto Sacchetti,⁵ Silvia Paradisi,⁵ Arnaldo Ferroni,⁶ Paul M. Curmi,⁷ Samuel N. Breit,⁸ and Michele Mazzanti¹

Dipartimenti di ¹Biologia Cellulare e dello Sviluppo, ²Scienze Cardiovascolari e Respiratorie, and ³Genetica e Biologia Molecolare, Università "La Sapienza", 00185 Rome, Italy, ⁴Dipartimento di Biologia, Università "Roma Tre", 00154 Rome, Italy, ⁵Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, 00185 Rome, Italy, ⁶Dipartimento di Scienze Biomolecolari e Biotecnologie, 20133 Milan, Italy, ⁷Initiative for Biomolecular Structure, School of Physics, University of New South Wales, Sydney 2052, Australia, and ⁸Centre for Immunology, St Vincent's Hospital and University of New South Wales, Sydney 2010, Australia

It is widely believed that the inflammatory events mediated by microglial activation contribute to several neurodegenerative processes. Alzheimer's disease, for example, is characterized by an accumulation of -amyloid protein (A) in neuritic plaques that are infiltrated by reactive microglia and astrocytes. Although A and its fragment 25-35 exert a direct toxic effect on neurons, they also activate microglia. Microglial activation is accompanied by morphological changes, cell proliferation, and release of various cytokines and growth factors. A number of scientific reports suggest that the increased proliferation of microglial cells is dependent on ionic membrane currents and in particular on chloride conductances. An unusual chloride ion channel known to be associated with macrophage activation is the chloride intracellular channel-1 (CLIC1). Here we show that A stimulation of neonatal rat microglia specifically leads to the increase in CLIC1 protein and to the functional expression of CLIC1 chloride conductance, both barely detectable on the plasma membrane of quiescent cells. CLIC1 protein expression in microglia increases after 24 hr of incubation with A, simultaneously with the production of reactive nitrogen intermediates and of tumor necrosis factor- (TNF-). We demonstrate that reducing CLIC1 chloride conductance by a specific blocker [IAA-94 (R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-oxy] acetic acid)] prevents neuronal apoptosis in neurons cocultured with A-treated microglia. Furthermore, we show that small interfering RNAs used to knock down CLIC1 expression prevent TNF- release induced by A stimulation. These results provide a direct link between A-induced microglial activation and CLIC1 functional expression.

Key words: Alzheimer; microglia; neurotoxicity; CLIC1; chloride channel; -amyloid

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Received Oct 23, 2003; revised April 21, 2004; accepted April 22, 2004.

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