Journal Article

Inflammatory Eicosanoids Increase Amyloid Precursor Protein Expression via Activation of Multiple Neuronal Receptors

James, Michael, Liu, Li, Xie, Sharon X., Herbst-Robinson, Katie J., Yao, Yuemang, Brunden, Kurt R.

2015

Overview

Senile plaques comprised of Aβ peptides are a hallmark of Alzheimer’s disease (AD) brain, as are activated glia that release inflammatory molecules, including eicosanoids. Previous studies have demonstrated that amyloid precursor protein (APP) and Aβ levels can be increased through activation of thromboxane A2-prostanoid (TP) receptors on neurons. We demonstrate that TP receptor regulation of APP expression depends on Gα q -signaling and conventional protein kinase C isoforms. Importantly, we discovered that Gα q -linked prostaglandin E2 and leukotriene D4 receptors also regulate APP expression. Prostaglandin E2 and thromboxane A2, as well as total APP levels, were found to be elevated in the brains of aged 5XFAD transgenic mice harboring Aβ plaques and activated glia, suggesting that increased APP expression resulted from eicosanoid binding to Gα q -linked neuronal receptors. Notably, inhibition of eicosanoid synthesis significantly lowered brain APP protein levels in aged 5XFAD mice. These results provide new insights into potential AD therapeutic strategies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1689/1283 / 631/378/1689/364 / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer's disease / Amyloid beta-Peptides - genetics / Amyloid beta-Peptides - metabolism / Amyloid beta-Protein Precursor - genetics / Amyloid beta-Protein Precursor - metabolism / Amyloid precursor protein / Animals / Brain - metabolism / Brain - pathology / Cells, Cultured / Dinoprostone - metabolism / Disease Models, Animal / Eicosanoids / Eicosanoids - metabolism / Female / Gene Expression / GTP-Binding Protein alpha Subunits, Gq-G11 - genetics / GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism / HEK293 Cells / Humanities and Social Sciences / Humans / Immunoblotting / Inflammation / Inflammation Mediators - metabolism / Isoforms / Kinases / Male / Mice, Transgenic / multidisciplinary / Neurodegenerative diseases / Neurons - metabolism / Peptides / Prostaglandin E2 / Protein kinase C / Protein Kinase C - genetics / Protein Kinase C - metabolism / Proteins / Rats / Receptors, Thromboxane A2, Prostaglandin H2 - genetics / Receptors, Thromboxane A2, Prostaglandin H2 - metabolism / Reverse Transcriptase Polymerase Chain Reaction / RNA Interference / Rodents / Science / Senile plaques / Thromboxane A2 / Thromboxane A2 - metabolism / Transgenic mice