Tags

Type your tag names separated by a space and hit enter

Beta-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.
J Neurosci 2009; 29(28):9078-89JN

Abstract

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.

Authors+Show Affiliations

Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19605645

Citation

Ma, Qiu-Lan, et al. "Beta-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." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 29, no. 28, 2009, pp. 9078-89.
Ma QL, Yang F, Rosario ER, et al. Beta-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. J Neurosci. 2009;29(28):9078-89.
Ma, Q. L., Yang, F., Rosario, E. R., Ubeda, O. J., Beech, W., Gant, D. J., ... Cole, G. M. (2009). Beta-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. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 29(28), pp. 9078-89. doi:10.1523/JNEUROSCI.1071-09.2009.
Ma QL, et al. Beta-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. J Neurosci. 2009 Jul 15;29(28):9078-89. PubMed PMID: 19605645.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Beta-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. 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, PY - 2009/7/17/entrez PY - 2009/7/17/pubmed PY - 2009/8/4/medline SP - 9078 EP - 89 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 29 IS - 28 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/19605645/Beta_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_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=19605645 DB - PRIME DP - Unbound Medicine ER -