-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

• DOI: 10.1523/jneurosci.1071-09.2009
• Publication Date: 2009-07-15T17:28:25Z
• Authors: Q.-L. Ma; F. Yang; E. R. Rosario; O. J. Ubeda; W. Beech; D. J. Gant; P. P. Chen; B. Hudspeth; C. Chen; Y. Zhao; H. V. Vinters; S. A. Frautschy; G. M. Cole
• Keywords: Aged, 80 and over; 2. Zero hunger; Amyloid beta-Peptides; Curcumin; Behavior, Animal; JNK Mitogen-Activated Protein Kinases; Mice, Transgenic; Middle Aged; Embryo, Mammalian; Hippocampus; Amyloid beta-Protein Precursor; Disease Models, Animal; Mice; 03 medical and health sciences; 0302 clinical medicine; Alzheimer Disease; Fatty Acids, Omega-3; Insulin Receptor Substrate Proteins; Animals; Humans; Enzyme Inhibitors; Cells, Cultured; Aged

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.