In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer%26apos;s disease through GSK3 beta and secretases

作者：Ignacio Diaz Hernandez Juan; Gomez Villafuertes Rosa; Leon Otegui Miriam; Hontecillas Prieto Lourdes; del Puerto Ana; Luis Trejo Jose; Javier Lucas Jose; Jose Garrido Juan; Gualix Javier; Teresa Miras Portugal Maria; Diaz Hernandez Miguel^*

来源：Neurobiology of Aging, 2012, 33(8): 1816-1828.

DOI：10.1016/j.neurobiolaging.2011.09.040

• P2X7
• Familiar Alzheimer%26apos
• s disease
• APP transgenic mice
• GSK-3
• alpha-secretase
• APP
• Amyloid plaques

beta-amyloid (A beta) peptide production from amyloid precursor protein (APP) is essential in the formation of the beta-amyloid plaques characteristic of Alzheimer%26apos;s disease. However, the extracellular signals that maintain the balance between nonpathogenic and pathologic forms of APP processing, mediated by alpha-secretase and beta-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 alpha-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 alpha-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%26apos;s disease (FAD).

• 出版日期2012-8