A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model.
Epidemiological studies suggest that increased intake of the omega-3 (n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimer's disease (AD). DHA levels are lower in serum and brains of AD patients, which could result from low dietary intake and/or PUFA oxidation. Because effects of DHA on Alzheimer pathogenesis, particularly on amyloidosis, are unknown, we used the APPsw (Tg2576) transgenic mouse model to evaluate the impact of dietary DHA on amyloid precursor protein (APP) processing and amyloid burden. Aged animals (17-19 months old) were placed in one of three groups until 22.5 months of age: control (0.09% DHA), low-DHA (0%), or high-DHA (0.6%) chow. beta-Amyloid (Abeta) ELISA of the detergent-insoluble extract of cortical homogenates showed that DHA-enriched diets significantly reduced total Abeta by >70% when compared with low-DHA or control chow diets. Dietary DHA also decreased Abeta42 levels below those seen with control chow. Image analysis of brain sections with an antibody against Abeta (amino acids 1-13) revealed that overall plaque burden was significantly reduced by 40.3%, with the largest reductions (40-50%) in the hippocampus and parietal cortex. DHA modulated APP processing by decreasing both alpha- and beta-APP C-terminal fragment products and full-length APP. BACE1 (beta-secretase activity of the beta-site APP-cleaving enzyme), ApoE (apolipoprotein E), and transthyretin gene expression were unchanged with the high-DHA diet. Together, these results suggest that dietary DHA could be protective against beta-amyloid production, accumulation, and potential downstream toxicity.
Lim
Giselle P
GP
Department of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Calon
Frédéric
F
Morihara
Takashi
T
Yang
Fusheng
F
Teter
Bruce
B
Ubeda
Oliver
O
Salem
Norman
N
Frautschy
Sally A
SA
Cole
Greg M
GM
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000178:diet therapy* / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western / Q000379:methods; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005227:Fatty Acids / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013223:Statistics as Topic
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D004042:Dietary Fats, Unsaturated; D005227:Fatty Acids; D010446:Peptide Fragments; D011228:Prealbumin; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D004281:Docosahexaenoic Acids; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse