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

• Published in: Neurobiology of aging 2012-08, Vol.33 (8), p.1816-1828
• Main Authors: Diaz-Hernandez, Juan Ignacio, Gomez-Villafuertes, Rosa, León-Otegui, Miriam, Hontecillas-Prieto, Lourdes, del Puerto, Ana, Trejo, Jose Luis, Lucas, Jose Javier, Garrido, Juan Jose, Gualix, Javier, Miras-Portugal, Maria Teresa, Diaz-Hernandez, Miguel
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - complications; Alzheimer Disease - enzymology; Amyloid plaques; Amyloid Precursor Protein Secretases - metabolism; Animals; APP; APP transgenic mice; Cell Line; Familiar Alzheimer's disease; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GSK-3; Humans; Internal Medicine; Mice; Mice, Transgenic; Neurology; P2X7; Plaque, Amyloid - complications; Plaque, Amyloid - enzymology; Purinergic P2X Receptor Antagonists - pharmacology; Receptors, Purinergic P2X7 - metabolism; Signal Transduction - drug effects; α-secretase
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2011.09.040

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).