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The Journal of Neuroscience, July 15, 2009, 29(28):9078-9089; doi:10.1523/JNEUROSCI.1071-09.2009

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Neurobiology of Disease
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

Qiu-Lan Ma,^1,4 Fusheng Yang,^1,4 Emily R. Rosario,^1,4 Oliver J. Ubeda,^1,4 Walter Beech,^1,4 Dana J. Gant,^1,4 Ping Ping Chen,^1,4 Beverly Hudspeth,^1,4 Cory Chen,^1,4 Yongle Zhao,^1,4 Harry V. Vinters,^2,3 Sally A. Frautschy,^1,2,4 and Greg M. Cole^1,2,4

¹Departments of Medicine, ²Neurology, and ³Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California 90095, and ⁴Geriatric Research and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Veterans Affairs Medical Center, North Hills, California 91343

Correspondence should be addressed to Greg. M. Cole, Veterans Affairs, Greater Los Angeles Healthcare System Research 151, Building 7, Room A101, 16111 Plummer Street, North Hills, CA 91343. Email: gmcole{at}ucla.edu

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.

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Received March 4, 2009; revised May 29, 2009; accepted June 15, 2009.

Correspondence should be addressed to Greg. M. Cole, Veterans Affairs, Greater Los Angeles Healthcare System Research 151, Building 7, Room A101, 16111 Plummer Street, North Hills, CA 91343. Email: gmcole{at}ucla.edu

This article has been cited by other articles:

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No therapeutic effect of dietary omega-3 fatty acid and curcumin in dementia and Alzheimer’s disease

Cesare Mancuso, et al.

J. Neurosci. Online, 27 Jul 2009 [Full text]

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