Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice

FASEB J. 2014 Oct;28(10):4312-23. doi: 10.1096/fj.14-251736. Epub 2014 Jun 24.

Abstract

Maternal choline supplementation (MCS) induces lifelong cognitive benefits in the Ts65Dn mouse, a trisomic mouse model of Down syndrome and Alzheimer's disease. To gain insight into the mechanisms underlying these beneficial effects, we conducted a study to test the hypothesis that MCS alters choline metabolism in adult Ts65Dn offspring. Deuterium-labeled methyl-d9-choline was administered to adult Ts65Dn and disomic (2N) female littermates born to choline-unsupplemented or choline-supplemented Ts65Dn dams. Enrichment of d9-choline metabolites (derived from intact choline) and d3 + d6-choline metabolites [produced when choline-derived methyl groups are used by phosphatidylethanolamine N-methyltransferase (PEMT)] was measured in harvested tissues. Adult offspring (both Ts65Dn and 2N) of choline-supplemented (vs. choline-unsupplemented) dams exhibited 60% greater (P≤0.007) activity of hepatic PEMT, which functions in de novo choline synthesis and produces phosphatidylcholine (PC) enriched in docosahexaenoic acid. Higher (P<0.001) enrichment of PEMT-derived d3 and d6 metabolites was detected in liver, plasma, and brain in both genotypes but to a greater extent in the Ts65Dn adult offspring. MCS also yielded higher (P<0.05) d9 metabolite enrichments in liver, plasma, and brain. These data demonstrate that MCS exerts lasting effects on offspring choline metabolism, including up-regulation of the hepatic PEMT pathway and enhanced provision of choline and PEMT-PC to the brain.

Keywords: Alzheimer's disease; Down syndrome; docosahexaenoic acid; fetal programming; phosphatidylcholine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Choline / administration & dosage
  • Choline / pharmacokinetics*
  • Choline / pharmacology
  • Choline / therapeutic use
  • Dietary Supplements
  • Docosahexaenoic Acids / metabolism
  • Down Syndrome / drug therapy
  • Down Syndrome / metabolism*
  • Female
  • Lipid Metabolism / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylcholines / metabolism
  • Phosphatidylethanolamine N-Methyltransferase / metabolism*
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Tissue Distribution

Substances

  • Phosphatidylcholines
  • Docosahexaenoic Acids
  • PEMT protein, mouse
  • Phosphatidylethanolamine N-Methyltransferase
  • Choline