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rdf:type |
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lifeskim:mentions |
umls-concept:C0010467,
umls-concept:C0015689,
umls-concept:C0031715,
umls-concept:C0034818,
umls-concept:C0037083,
umls-concept:C0205263,
umls-concept:C0248813,
umls-concept:C0301625,
umls-concept:C0599219,
umls-concept:C1710082,
umls-concept:C1710236,
umls-concept:C1720655,
umls-concept:C1947974,
umls-concept:C2353566,
umls-concept:C2700455
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pubmed:issue |
28
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pubmed:dateCreated |
2009-7-16
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pubmed:abstractText |
Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. Increased phospho-IRS-1 is found in AD brain and insulin-resistant tissues from diabetics. Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. This was accompanied by improvement in Y-maze performance. Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Protein Precursor,
http://linkedlifedata.com/resource/pubmed/chemical/Curcumin,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Fatty Acids, Omega-3,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin Receptor Substrate Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/JNK Mitogen-Activated Protein...,
http://linkedlifedata.com/resource/pubmed/chemical/PSEN1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Presenilin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Serine,
http://linkedlifedata.com/resource/pubmed/chemical/amyloid beta-protein (1-42),
http://linkedlifedata.com/resource/pubmed/chemical/tau Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1529-2401
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pubmed:author |
pubmed-author:AliM VMV,
pubmed-author:BeechWalterW,
pubmed-author:ChenPing PingPP,
pubmed-author:ColeGreg MGM,
pubmed-author:FrautschySally ASA,
pubmed-author:GantDana JDJ,
pubmed-author:HudspethBeverlyB,
pubmed-author:MaQiu-LanQL,
pubmed-author:RosarioEmily RER,
pubmed-author:UbedaOliver JOJ,
pubmed-author:VintersHarry VHV,
pubmed-author:YangFushengF,
pubmed-author:ZhaoYongleY
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
29
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
9078-89
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pubmed:dateRevised |
2011-5-5
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pubmed:meshHeading |
pubmed-meshheading:19605645-Aged,
pubmed-meshheading:19605645-Aged, 80 and over,
pubmed-meshheading:19605645-Alzheimer Disease,
pubmed-meshheading:19605645-Amyloid beta-Peptides,
pubmed-meshheading:19605645-Amyloid beta-Protein Precursor,
pubmed-meshheading:19605645-Animals,
pubmed-meshheading:19605645-Behavior, Animal,
pubmed-meshheading:19605645-Cells, Cultured,
pubmed-meshheading:19605645-Curcumin,
pubmed-meshheading:19605645-Disease Models, Animal,
pubmed-meshheading:19605645-Embryo, Mammalian,
pubmed-meshheading:19605645-Enzyme Inhibitors,
pubmed-meshheading:19605645-Fatty Acids, Omega-3,
pubmed-meshheading:19605645-Hippocampus,
pubmed-meshheading:19605645-Humans,
pubmed-meshheading:19605645-Insulin Receptor Substrate Proteins,
pubmed-meshheading:19605645-JNK Mitogen-Activated Protein Kinases,
pubmed-meshheading:19605645-Mice,
pubmed-meshheading:19605645-Mice, Transgenic,
pubmed-meshheading:19605645-Middle Aged,
pubmed-meshheading:19605645-Neurons,
pubmed-meshheading:19605645-Peptide Fragments,
pubmed-meshheading:19605645-Phosphorylation,
pubmed-meshheading:19605645-Postmortem Changes,
pubmed-meshheading:19605645-Presenilin-1,
pubmed-meshheading:19605645-Rats,
pubmed-meshheading:19605645-Rats, Sprague-Dawley,
pubmed-meshheading:19605645-Serine,
pubmed-meshheading:19605645-Signal Transduction,
pubmed-meshheading:19605645-tau Proteins
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pubmed:year |
2009
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pubmed:articleTitle |
Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin.
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pubmed:affiliation |
Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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