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In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer's disease through GSK3β and secretases

AuthorsDíaz-Hernández, J. I.; Gómez-Villafuertes, Rosa; León-Otegui, M.; Hontecillas-Prieto, L.; Puerto, Ana del; Trejo, José L. ; Lucas, J. J.; Garrido Jurado, Juan José ; Gualix, J.; Miras-Portugal, María Teresa; Díaz-Hernández, Miguel
Issue Date2012
CitationNeurobiology of Aging 33: 1816- 1828 (2012)
Abstractβ-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). © 2012 Elsevier Inc..
Identifiersdoi: 10.1016/j.neurobiolaging.2011.09.040
issn: 0197-4580
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