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

Sci Rep. 2015 Dec 17;5:18286. doi: 10.1038/srep18286.

Abstract

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 Gαq-signaling and conventional protein kinase C isoforms. Importantly, we discovered that Gαq-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 Gαq-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Cells, Cultured
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Eicosanoids / metabolism*
  • Female
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Inflammation Mediators / metabolism
  • Male
  • Mice, Transgenic
  • Neurons / metabolism*
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • RNA Interference
  • Rats
  • Receptors, Thromboxane A2, Prostaglandin H2 / genetics
  • Receptors, Thromboxane A2, Prostaglandin H2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thromboxane A2 / metabolism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Eicosanoids
  • Inflammation Mediators
  • Receptors, Thromboxane A2, Prostaglandin H2
  • Thromboxane A2
  • Protein Kinase C
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Dinoprostone