RT Journal Article
SR Electronic
T1 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
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9078
OP 9089
DO 10.1523/JNEUROSCI.1071-09.2009
VO 29
IS 28
A1 Ma, Qiu-Lan
A1 Yang, Fusheng
A1 Rosario, Emily R.
A1 Ubeda, Oliver J.
A1 Beech, Walter
A1 Gant, Dana J.
A1 Chen, Ping Ping
A1 Hudspeth, Beverly
A1 Chen, Cory
A1 Zhao, Yongle
A1 Vinters, Harry V.
A1 Frautschy, Sally A.
A1 Cole, Greg M.
YR 2009
UL http://www.jneurosci.org/content/29/28/9078.abstract
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.