Structural insight into the differential effects of omega-3 and omega-6 fatty acids on the production of Abeta peptides and amyloid plaques

J Biol Chem. 2011 Feb 25;286(8):6100-7. doi: 10.1074/jbc.M110.183608. Epub 2010 Oct 22.


Several studies have shown the protective effects of dietary enrichment of various lipids in several late-onset animal models of Alzheimer Disease (AD); however, none of the studies has determined which structure within a lipid determines its detrimental or beneficial effects on AD. High-sensitivity enzyme-linked immunosorbent assay (ELISA) shows that saturated fatty acids (SFAs), upstream omega-3 FAs, and arachidonic acid (AA) resulted in significantly higher secretion of both Aβ 40 and 42 peptides compared with long chain downstream omega-3 and monounsaturated FAs (MUFA). Their distinct detrimental action is believed to be due to a structural template found in their fatty acyl chains that lack SFAs, upstream omega-3 FAs, and AA. Immunoblotting experiments and use of APP-C99-transfected COS-7 cells suggest that FA-driven altered production of Aβ is mediated through γ-secretase cleavage of APP. An early-onset AD transgenic mouse model expressing the double-mutant form of human amyloid precursor protein (APP); Swedish (K670N/M671L) and Indiana (V717F), corroborated in vitro findings by showing lower levels of Aβ and amyloid plaques in the brain, when they were fed a low fat diet enriched in DHA. Our work contributes to the clarification of aspects of structure-activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid / genetics
  • Amyloid / metabolism*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / biosynthesis*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • COS Cells
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Fatty Acids, Omega-3 / metabolism
  • Fatty Acids, Omega-3 / pharmacology*
  • Fatty Acids, Omega-6 / metabolism
  • Fatty Acids, Omega-6 / pharmacology*
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Peptides / genetics
  • Peptides / metabolism*


  • APP protein, human
  • Amyloid
  • Amyloid beta-Protein Precursor
  • Fatty Acids, Omega-3
  • Fatty Acids, Omega-6
  • Peptides
  • Amyloid Precursor Protein Secretases