title: In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer's disease through GSK3β and secretases.
abstract: β-Amyloid (Aβ) peptide production from amyloid precursor protein (APP) is essential in the formation of the β-amyloid plaques characteristic of Alzheimer's disease. However, the extracellular signals that maintain the balance between nonpathogenic and pathologic forms of APP processing, mediated by α-secretase and β-secretase respectively, remain poorly understood. In the present work, we describe regulation of the processing of APP via the adenosine triphosphate (ATP) receptor P2X7R. In 2 different cellular lines, the inhibition of either native or overexpressed P2X7R increased α-secretase activity through inhibition of glycogen synthase kinase 3 (GSK-3). In vivo inhibition of the P2X7R in J20 mice, transgenic for mutant human APP, induced a significant decrease in the number of hippocampal amyloid plaques. This reduction correlated with a decrease in glycogen synthase kinase 3 activity in J20 mice, increasing the proteolytic processing of APP through an increase in α-secretase activity. The in vivo findings presented here demonstrate for the first time the therapeutic potential of P2X7R antagonism in the treatment of familiar Alzheimer's disease (FAD).
authors: Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain.
authors: Juan Ignacio
authors: JI
authors: Diaz-Hernandez
authors: Rosa
authors: R
authors: Gomez-Villafuertes
authors: Miriam
authors: M
authors: León-Otegui
authors: Lourdes
authors: L
authors: Hontecillas-Prieto
authors: Ana
authors: A
authors: Del Puerto
authors: Jose Luis
authors: JL
authors: Trejo
authors: Jose Javier
authors: JJ
authors: Lucas
authors: Juan Jose
authors: JJ
authors: Garrido
authors: Javier
authors: J
authors: Gualix
authors: Maria Teresa
authors: MT
authors: Miras-Portugal
authors: Miguel
authors: M
authors: Diaz-Hernandez
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000150:complications / Q000201:enzymology*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases