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

J Neurosci. 2009 Jul 15;29(28):9078-89. doi: 10.1523/JNEUROSCI.1071-09.2009.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / diet therapy
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / pharmacology*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Behavior, Animal
  • Cells, Cultured
  • Curcumin / pharmacology*
  • Curcumin / therapeutic use
  • Disease Models, Animal
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Fatty Acids, Omega-3 / pharmacology*
  • Fatty Acids, Omega-3 / therapeutic use
  • Hippocampus / cytology
  • Humans
  • Insulin Receptor Substrate Proteins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Neurons / drug effects*
  • Peptide Fragments / pharmacology*
  • Phosphorylation / drug effects
  • Postmortem Changes
  • Presenilin-1 / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Serine / metabolism
  • Signal Transduction / drug effects*
  • tau Proteins / metabolism*


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Enzyme Inhibitors
  • Fatty Acids, Omega-3
  • Insulin Receptor Substrate Proteins
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Serine
  • JNK Mitogen-Activated Protein Kinases
  • Curcumin