PT  - JOURNAL ARTICLE
AU  - Ma, Qiu-Lan
AU  - Yang, Fusheng
AU  - Rosario, Emily R.
AU  - Ubeda, Oliver J.
AU  - Beech, Walter
AU  - Gant, Dana J.
AU  - Chen, Ping Ping
AU  - Hudspeth, Beverly
AU  - Chen, Cory
AU  - Zhao, Yongle
AU  - Vinters, Harry V.
AU  - Frautschy, Sally A.
AU  - Cole, Greg M.
TI  - β-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
AID  - 10.1523/JNEUROSCI.1071-09.2009
DP  - 2009 Jul 15
TA  - The Journal of Neuroscience
PG  - 9078--9089
VI  - 29
IP  - 28
4099  - http://www.jneurosci.org/content/29/28/9078.short
4100  - http://www.jneurosci.org/content/29/28/9078.full
SO  - J. Neurosci.2009 Jul 15; 29
AB  - Both insulin resistance (type II diabetes) and β-amyloid (Aβ) oligomers are implicated in Alzheimer's disease (AD). Here, we investigate the role of Aβ 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 Aβ 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 Aβ 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.