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Activation of Microglia by Amyloid β Requires P2X₇ Receptor Expression¹

Juana M. Sanz^*, Paola Chiozzi^,, Davide Ferrari^,, Marilena Colaianna, Marco Idzko^¶, Simonetta Falzoni^,, Renato Fellin^*, Luigia Trabace and Francesco Di Virgilio^2,,

^* Department of Clinical and Experimental Medicine, Section of Internal Medicine, Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy; Department of Biomedical Sciences, University of Foggia, Italy; and ^¶ Department of Pulmonary Medicine, University Hospital, Freiburg, Germany

Extracellular ATP is a mediator of intercellular communication and a danger signal. Release of this and other nucleotides modulates microglia responses via P2Y and P2X receptors, among which the P2X₇ subtype stands out for its proinflammatory activity and for up-regulation in a transgenic model of Alzheimer disease and in brains from Alzheimer disease patients. Here we show that amyloid β (Aβ) triggered increases in intracellular Ca²⁺ ([Ca²⁺]_i), ATP release, IL-1β secretion, and plasma membrane permeabilization in microglia from wild-type but not from P2X₇-deleted mice. Likewise, intra-hippocampal injection of Aβ caused a large accumulation of IL-1β in wild-type but not in P2X₇^–/– mice. These observations suggest that Aβ activates a purinergic autocrine/paracrine stimulatory loop of which the P2X₇ receptor is an obligate component. Identification of the P2X₇ receptor as a non-dispensable factor of Aβ-mediated microglia stimulation may open new avenues for the treatment of Alzheimer disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants by the Italian Ministry of Education, University and Scientific Research, the Italian Association for Cancer Research, the Italian Space Agency, Telethon of Italy (GGP06070), the Commission of European Communities (7th Framework Program HEALTH-F2-2007-202231), the Regione Emilia Romagna (Research Programs "Innovative approaches to the diagnosis of inflammatory diseases" and "Moniter"), and local funds from the University of Ferrara.

² Address correspondence and reprint requests to Dr Francesco Di Virgilio, Department of Experimental and Diagnostic Medicine, Section of General Pathology, University of Ferrara, Via Borsari 46, 44100 Ferrara, Italy. E-mail address: fdv{at}unife.it

³ Abbreviations used in this paper: Aβ, amyloid β; iAβ, scrambled amyloid β; [Ca²⁺]_i, intracellular Ca²⁺ concentration; oATP, oxidized ATP; LDH, lactic dehydrogenase; R-N13, ATP-resistant N-13 cells; wtN-13, wild-type N-13 cells; aCSF, artificial CSF.