Activation of Microglia by Amyloid {beta} Requires P2X7 Receptor Expression

• Published in: The Journal of immunology (1950) 2009-04, Vol.182 (7), p.4378-4385
• Main Authors: Sanz, Juana M, Chiozzi, Paola, Ferrari, Davide, Colaianna, Marilena, Idzko, Marco, Falzoni, Simonetta, Fellin, Renato, Trabace, Luigia, Di Virgilio, Francesco
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Amyloid beta-Peptides - metabolism; Animals; Calcium - metabolism; Cell Membrane Permeability - physiology; Interleukin-1beta - metabolism; Mice; Mice, Knockout; Microglia - metabolism; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2 - metabolism; Receptors, Purinergic P2X7
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0803612

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 P2X(7) 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 beta (Abeta) triggered increases in intracellular Ca(2+) ([Ca(2+)](i)), ATP release, IL-1beta secretion, and plasma membrane permeabilization in microglia from wild-type but not from P2X(7)-deleted mice. Likewise, intra-hippocampal injection of Abeta caused a large accumulation of IL-1beta in wild-type but not in P2X(7)(-/-) mice. These observations suggest that Abeta activates a purinergic autocrine/paracrine stimulatory loop of which the P2X(7) receptor is an obligate component. Identification of the P2X(7) receptor as a non-dispensable factor of Abeta-mediated microglia stimulation may open new avenues for the treatment of Alzheimer disease.