Lipidomics of Alzheimer’s disease: a liver peroxisomal dysfunction in the metabolism of omega-3 fatty acids

¹ University of California Irvine, Department of Pharmacology, University of California, Irvine, CA 92697-4625
² Department of Biological Chemistry, University of California, Irvine, CA 92697-4625
³ United States Unit of Drug Discovery and Development, Italian Institute of Technology, Genoa, Italy

Abstract

Reduced brain levels of docosahexaenoic acid (DHA), a neurotrophic and neuroprotective fatty acid, might contribute to cognitive and visual decline. A multiorgan lipidomic approach revealed that the levels of free DHA, DHA-containing phospholipids precursors and DHA-metabolites were decreased in various brain regions of subjects with Alzheimer’s disease (AD), compared to control subjects. Furthermore, liver DHA content was lower in AD patients than control subjects. Shorter chain omega-3 fatty acids precursors for DHA, were elevated in liver of AD patients, whereas expression of peroxisomal D-bifunctional protein, which catalyzes the conversion of tetracosahexaenoic acid into DHA, was selectively reduced. Lower DHA levels in the liver were associated with cognitive impairment and with higher prevalence of eye-diseases. The evidence presented herein indicate that a deficit in liver biosynthesis of DHA possibly lessens the flux of this neuroprotective fatty acid to brain and eyes, contributing to cognitive and visual impairments.