-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
Open accessAbstract
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.
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In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK.
“In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK [2, 35–41, 43, 44].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [38]
Figure 5 reports increased tau Ser422 phosphorylation after Aβ oligomer treatment in cultured neurons, and the Discussion reports increased phosphorylated tau in a 3xTg-AD mouse model under a high-fat diet. The Discussion says GSK3β is known to be activated by Aβ, but predicts rather than demonstrates its activation through the mechanism studied here. The cited passages do not establish that Aβ co-expression increases active GSK3 and PAR-1/MARK; PAR-1/MARK is not reported. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD.
“Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD [2, 35–41].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [38]
The Results section on cultured hippocampal neurons (page unavailable) reports that Aβ42 oligomers significantly increased tau phosphorylation at Ser422, a site the paper associates with AD neurodegeneration. The paper also reports increased tau Ser422 phosphorylation in 3xTg-AD mice on a high-fat diet, but it does not establish that Aβ itself caused that increase in vivo. (LLM, conf=0.84)
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- Authors
- Ma, Q.-L., Yang, F., Rosario, E. R., Ubeda, O. J., Beech, W., Gant, D. J., Chen, P. P., Hudspeth, B., Chen, C., Zhao, Y., Vinters, H. V., Frautschy, S. A., & Cole, G. M.
- Affiliations
- University of California, Los Angeles (US)
- Veterans Health Administration (US)
- VA Greater Los Angeles Healthcare System (US)
- Corresponding author
- Cole, G. M.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-07-15
- Volume
- 29
- Issue
- 28
- Pages
- 9078-9089
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3849615
- OpenAlex
- W1971116512
- Cited by
- 536
- References
- 16
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 22 · 2023: 23 · 2022: 21 · 2021: 22 · 2020: 33 · 2019: 44 · 2018: 39 · 2017: 31 · 2016: 40 · 2015: 55 · 2014: 36 · 2013: 32 · 2012: 34
- FWCI
- 20.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health
- National Institute on Aging (R01 AG16570, U01AG028583, P50AG016570, R01AG013741, R01AG021975, AG13471)
- National Center for Complementary and Integrative Health (R01AT003008, R01AT006816)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Keywords
- amyloid-beta oligomers, Alzheimer's disease, c-Jun N-terminal kinase, IRS-1, tau phosphorylation, insulin resistance, docosahexaenoic acid, omega-3 fatty acids, curcumin, fish oil, hippocampal neurons, 3xTg-AD mice, high-fat diet, omega-6 fatty acids, cognitive impairment, neuroprotection
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Behavior, Animal, Cells, Cultured, Curcumin, Disease Models, Animal, Embryo, Mammalian, Enzyme Inhibitors, Hippocampus, Humans, Mice, Transgenic, Middle Aged, Neurons, Peptide Fragments, Phosphorylation, Postmortem Changes, Serine, Signal Transduction, Fatty Acids, Omega-3, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Rats, Sprague-Dawley, JNK Mitogen-Activated Protein Kinases, Mice, Rats, Presenilin-1, Insulin Receptor Substrate Proteins
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