Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease.
Epidemiological data indicate that low n-3 polyunsaturated fatty acids (PFA) intake is a readily manipulated dietary risk factor for Alzheimer's disease (AD). Studies in animals confirm the deleterious effect of n-3 PFA depletion on cognition and on dendritic scaffold proteins. Here, we show that in transgenic mice overexpressing the human AD gene APPswe (Tg2576), safflower oil-induced n-3 PFA deficiency caused a decrease in N-methyl-D-aspartate (NMDA) receptor subunits, NR2A and NR2B, in the cortex and hippocampus with no loss of the presynaptic markers, synaptophysin and synaptosomal-associated protein 25 (SNAP-25). n-3 PFA depletion also decreased the NR1 subunit in the hippocampus and Ca2+/calmodulin-dependent protein kinase (CaMKII) in the cortex of Tg2576 mice. These effects of dietary n-3 PFA deficiency were greatly amplified in Tg2576 mice compared to nontransgenic mice. Loss of the NR2B receptor subunit was not explained by changes in mRNA expression, but correlated with p85alpha phosphatidylinositol 3-kinase levels. Most interestingly, n-3 PFA deficiency dramatically increased levels of protein fragments, corresponding to caspase/calpain-cleaved fodrin and gelsolin in Tg2576 mice. This effect was minimal in nontransgenic mice suggesting that n-3 PFA depletion potentiated caspase activation in the Tg2576 mouse model of AD. Dietary supplementation with docosahexaenoic acid (DHA; 22 : 6n-3) partly protected from NMDA receptor subunit loss and accumulation of fodrin and gelsolin fragments but fully prevented CaMKII decrease. The marked effect of dietary n-3 PFA on NMDA receptors and caspase/calpain activation in the cortex of an animal model of AD provide new insights into how dietary essential fatty acids may influence cognition and AD risk.
Calon
Frédéric
F
Department of Medicine, University of California, Los Angeles, California, USA.
Lim
Giselle P
GP
Morihara
Takashi
T
Yang
Fusheng
F
Ubeda
Oliver
O
Salem
Norman
N
Frautschy
Sally A
SA
Cole
Greg M
GM
D000470:Alkaloids / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D004038:Diet, Reducing / Q000379:methods; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D005227:Fatty Acids / Q000032:analysis; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated / Q000172:deficiency*; D005260:Female; D018260:Gelsolin / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000145:classification / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013223:Statistics as Topic; D050825:Synaptosomal-Associated Protein 25; D013997:Time Factors; D014280:Triglycerides / Q000172:deficiency*; D051025:bcl-Associated Death Protein
D000470:Alkaloids; D016564:Amyloid beta-Protein Precursor; C494819:BAD protein, human; C494820:Bad protein, mouse; D002352:Carrier Proteins; D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D018260:Gelsolin; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C494208:SNAP25 protein, human; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D014280:Triglycerides; D051025:bcl-Associated Death Protein; C077446:Pikasol; C056118:fordine; D004281:Docosahexaenoic Acids; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002154:Calpain; D020169:Caspases