期刊
JOURNAL OF NEUROSCIENCE
卷 29, 期 28, 页码 9078-9089出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1071-09.2009
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资金
- National Institutes of Health (NIH) [R01 AT003008]
- National Institute on Aging-NIH [R01 AG16570, AG13471, U01 AG028583, R01 AG021975]
- Alzheimer's Association [NIRG-07-59659]
- Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine
Both insulin resistance (type II diabetes) and beta-amyloid (A beta) oligomers are implicated in Alzheimer's disease (AD). Here, we investigate the role of A beta 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 A beta 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 A beta 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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