Activation of microglia by amyloid {beta} requires P2X7 receptor expression.
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.
Sanz
Juana M
JM
Department of Clinical and Experimental Medicine, University of Ferrara, Italy.
Chiozzi
Paola
P
Ferrari
Davide
D
Colaianna
Marilena
M
Idzko
Marco
M
Falzoni
Simonetta
S
Fellin
Renato
R
Trabace
Luigia
L
Di Virgilio
Francesco
F
D000255:Adenosine Triphosphate / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7
D016229:Amyloid beta-Peptides; D053583:Interleukin-1beta; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D002118:Calcium