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
Autor: | Sally A. Frautschy, Emily R. Rosario, Ping-Ping Chen, Fusheng Yang, Beverly Hudspeth, Cory Chen, Dana J. Gant, Yongle Zhao, Greg M. Cole, Oliver J. Ubeda, Harry V. Vinters, Qiu-Lan Ma, Walter Beech |
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Rok vydání: | 2009 |
Předmět: |
medicine.medical_specialty
Curcumin medicine.medical_treatment Mice Transgenic tau Proteins Hippocampus Rats Sprague-Dawley Amyloid beta-Protein Precursor Mice Insulin resistance Alzheimer Disease Insulin receptor substrate Internal medicine Fatty Acids Omega-3 Presenilin-1 Serine medicine Animals Humans Enzyme Inhibitors Phosphorylation Cells Cultured Aged Aged 80 and over Neurons Amyloid beta-Peptides Behavior Animal biology Kinase General Neuroscience Insulin c-jun JNK Mitogen-Activated Protein Kinases Articles Middle Aged Embryo Mammalian medicine.disease Peptide Fragments Rats Disease Models Animal Insulin receptor Endocrinology Docosahexaenoic acid Postmortem Changes Insulin Receptor Substrate Proteins biology.protein Signal Transduction |
Zdroj: | Journal of Neuroscience. 29:9078-9089 |
ISSN: | 1529-2401 0270-6474 |
DOI: | 10.1523/jneurosci.1071-09.2009 |
Popis: | 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. |
Databáze: | OpenAIRE |
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