Structural insight into the differential effects of omega-3 and omega-6 fatty acids on the production of Abeta peptides and amyloid plaques.
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.
Zentrum für Molekulare Biologie Heidelberg, University of Heidelberg, Heidelberg, Germany. zamtul@uwo.ca
Zareen
Z
Amtul
Markus
M
Uhrig
Richard F
RF
Rozmahel
Konrad
K
Beyreuther
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D015525:Fatty Acids, Omega-3 / Q000378:metabolism / Q000494:pharmacology*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D010455:Peptides / Q000235:genetics / Q000378:metabolism*
C545487:APP protein, human; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D010455:Peptides; D053829:Amyloid Precursor Protein Secretases