Cornel Iridoid Glycoside Inhibits Tau Hyperphosphorylation via Regulating Cross-Talk Between GSK-3β and PP2A Signaling
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Neurofibrillary pathology contributes to neuronal dysfunction and correlates with the clinical progression of Alzheimer’s disease (AD). Tau phosphorylation is mainly regulated by a balance of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) activities. Cornel iridoid glycoside (CIG) is a main component extracted from Cornus officinalis. The purpose of this study was to investigate the effects of CIG on GSK-3β and PP2A, thus to explore the mechanisms of CIG to inhibit tau hyperphosphorylation. The rat model of tau hyperphosphorylation was established by intraventricular injection of wortmannin and GF-109203X (GFX) to activate GSK-3β. The results showed that intragastrical administration of CIG inhibited tau hyperphosphorylation in the brain of rats induced by wortmannin/GFX. The results in vivo and in vitro exhibited that CIG inhibited tau hyperphosphorylation and GSK-3β over-activation. In the mechanism of action, CIG’s attenuating GSK-3β activity was found to be dependent on PI3K/AKT signaling pathway. PP2A catalytic C subunit (PP2Ac) siRNA abrogated the effect of CIG on PI3K/AKT/GSK-3β. Additionally and crucially, we also found that CIG inhibited the demethylation of PP2Ac at Leu309 in vivo and in vitro. It enhanced PP2A activity, decreased tau hyperphosphorylation, and protected cell morphology in okadaic acid (OA)-induced cell model in vitro. PP2Ac siRNA abated the inhibitory effect of CIG on tau hyperphosphorylation. Moreover, CIG inhibited protein phosphatase methylesterase-1 (PME-1) and demethylation of PP2Ac, enhanced PP2A activity, and decreased tau hyperphosphorylation in PME-1-transfectd cells. Taken together, CIG inhibited GSK-3β activity via promoting P13K/AKT and PP2A signaling pathways. In addition, CIG also elevated PP2A activity via inhibiting PME-1-induced PP2Ac demethylation to inhibit GSK-3β activity, thus regulated the cross-talk between GSK-3β and PP2A signaling and consequently inhibited tau hyperphosphorylation. These results suggest that CIG may be a promising agent for AD therapy.
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CIG inhibits GSK-3β activity by activating the PI3K/AKT and PP2A signalling pathways.
“CIG inhibits GSK-3β activity by activating the P13K/AKT and PP2A signalling pathways.”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [184]
CIG may be a promising therapeutic agent for AD treatment.
“These results suggest that CIG may be a promising therapeutic agent for AD treatment [184].”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [184]
Natural products such as caffeine, CIG, and catechins have been shown to inhibit abnormal aggregation of tau protein.
“Natural products, such as caffeine, CIG, and catechins [184], have been shown to inhibit the abnormal aggregation of tau protein”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [184]
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Cites
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
The phosphatidylinositol 3-Kinase–AKT pathway in human cancer
Vivanco, I., & Sawyers, C. L. (2002) · Nature reviews. Cancer · doi:10.1038/nrc839 · Cited by 6,041 · see citing works
Lee, V. M.-Y., Goedert, M., & Trojanowski, J. Q. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1121 · Cited by 2,480 · see citing works
Alzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424 · see citing works
Molecular cloning and expression of glycogen synthase kinase‐3/factor A.
Woodgett, J. R. (1990) · The EMBO Journal · doi:10.1002/j.1460-2075.1990.tb07419.x · Cited by 1,362 · see citing works
Hoover, B. R., Reed, M. N., Su, J., Penrod, R. D., Kotilinek, L. A., Grant, M. K., Pitstick, R., Carlson, G. A., Lanier, L. M., Yuan, L.-L., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.030 · Cited by 1,118 · see citing works
Tau phosphorylation: the therapeutic challenge for neurodegenerative disease
Hanger, D. P., Anderton, B. H., & Noble, W. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.01.003 · Cited by 965 · see citing works
Glycogen synthase kinase-3 (GSK3): Inflammation, diseases, and therapeutics
Jope, R. S., Yuskaitis, C. J., & Beurel, E. (2007) · Neurochemical Research · doi:10.1007/s11064-006-9128-5 · Cited by 774 · see citing works
Liu, F., Grundke‐Iqbal, I., Iqbal, K., & Gong, C. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04391.x · Cited by 759 · see citing works
Wymann, M. P., Bulgarelli-Leva, G., Zvelebil, M., Pirola, L., Vanhaesebroeck, B., Waterfield, M. D., & Panayotou, G. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.4.1722 · Cited by 679 · see citing works
Phosphoprotein Phosphatase Activities in Alzheimer Disease Brain
Gong, C., Singh, T. J., Grundke‐Iqbal, I., & Iqbal, K. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb03603.x · Cited by 527 · see citing works
Protein phosphatase 2A regulatory subunits and cancer
Eichhorn, P. J. A., Creyghton, M. P., & Bernards, R. (2009) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2008.05.005 · Cited by 513 · see citing works
Structure and Pathology of Tau Protein in Alzheimer Disease
Kolarova, M., García‐Sierra, F., Bartoš, A., Říčný, J., & Řı́pová, D. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/731526 · Cited by 473 · see citing works
The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy
McGeer, P. L., & McGeer, E. G. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1177-7 · Cited by 467 · see citing works
Phosphatase Activity Toward Abnormally Phosphorylated τ: Decrease in Alzheimer Disease Brain
Gong, C., Shaikh, S., Wang, J., Zaidi, T., Grundke, I., & Iqbal, K. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.65020732.x · Cited by 440 · see citing works
Distribution, Levels, and Activity of Glycogen Synthase Kinase-3 in the Alzheimer Disease Brain
PEI, J.-J., TANAKA, T., TUNG, Y.-C., BRAAK, E., IQBAL, K., & GRUNDKE-IQBAL, I. (1997) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199701000-00007 · Cited by 371 · see citing works
Murray, M. E., Lowe, V. J., Graff-Radford, N. R., Liesinger, A. M., Cannon, A., Przybelski, S. A., Rawal, B., Parisi, J. E., Petersen, R. C., Kantarci, K., et al. (2015) · Brain · doi:10.1093/brain/awv050 · Cited by 324 · see citing works
PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer's Disease Hippocampus
Vogelsberg-Ragaglia, V., Schuck, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2001) · Experimental Neurology · doi:10.1006/exnr.2001.7630 · Cited by 281 · see citing works
Dietary regulation of PI3K/AKT/GSK-3β pathway in Alzheimer’s disease
Kitagishi, Y., Nakanishi, A., Ogura, Y., & Matsuda, S. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt265 · Cited by 246 · see citing works
Has the amyloid cascade hypothesis for Alzheimer's disease been proved?
Hardy, J. (2006) · Current Alzheimer Research · doi:10.2174/156720506775697098 · Cited by 242 · see citing works
Sontag, E., Luangpirom, A., Hladik, C., Mudrak, I., Ogris, E., Speciale, S., & White, C. L. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.4.287 · Cited by 228 · see citing works
AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation
Li, X., Lv, B.-L., Xie, J., Liu, J., Zhou, X., & Wang, J. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.02.003 · Cited by 207 · see citing works
Self-citationStructural mechanism of demethylation and inactivation of protein phosphatase 2A
Xing, Y., Li, Z., Chen, Y., Stock, J. B., Jeffrey, P. D., & Shi, Y. (2008) · Cell · doi:10.1016/j.cell.2008.02.041 · Cited by 206 · see citing works
Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK‐3β
Liu, F., Iqbal, K., Grundke, I., & Gong, C. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03487-7 · Cited by 197 · see citing works
Sontag, E., Hladik, C. L., Montgomery, L. G., Luangpirom, A., Mudrak, I., Ogris, E., & White, C. L. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.10.1080 · Cited by 191 · see citing works
Boutajangout, A., Leroy, K., Authelet, M., Anderton, B. H., Brion, J., & Woodgett, J. R. (2002) · Acta Neuropathologica · doi:10.1007/s004010100435 · Cited by 186 · see citing works
Wu, J., Tolstykh, T., Lee, J., Boyd, K., Stock, J. B., & Broach, J. R. (2000) · The EMBO Journal · doi:10.1093/emboj/19.21.5672 · Cited by 186 · see citing works
PP2A Regulates Tau Phosphorylation Directly and also Indirectly via Activating GSK-3β
Qian, W., Shi, J., Yin, X., Iqbal, K., Grundke-Iqbal, I., Gong, C., & Liu, F. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-1317 · Cited by 185 · see citing works
Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus
Zhang, C.-E., Tian, Q., Wei, W., Peng, J.-H., Liu, G., Zhou, X., Wang, Q., Wang, D. W., & Wang, J. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.04.015 · Cited by 159 · see citing works
Self-citationThe structural basis for tight control of PP2A methylation and function by LCMT-1
Stanevich, V., Jiang, L., Satyshur, K. A., Li, Y., Jeffrey, P. D., Li, Z., Menden, P., Semmelhack, M. F., & Xing, Y. (2011) · Molecular Cell · doi:10.1016/j.molcel.2010.12.030 · Cited by 142 · see citing works
Self-citationSun, X., Wei, Y., Xiong, Y., Wang, X., Xie, A., Wang, X., Yang, Y., Wang, Q., Lu, Y., Liu, R., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.309070 · Cited by 137 · see citing works
Self-citationCross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation
Wang, Y., Yang, R., Gu, J., Yin, X., Jin, N., Xie, S., Wang, Y., Chang, H., Qian, W., Shi, J., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.07.035 · Cited by 134 · see citing works
Phosphoprotein Phosphatase 2A: A Novel Druggable Target for Alzheimer’s Disease
Voronkov, M. V., Braithwaite, S. P., & Stock, J. B. (2011) · Future Medicinal Chemistry · doi:10.4155/fmc.11.47 · Cited by 121 · see citing works
Yao, R., Zhang, L., Wang, W., & Li, L. (2009) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2008.12.010 · Cited by 103 · see citing works
Self-citationLongin, S., Jordens, J., MARTENS, E., Stevens, I., Janssens, V., Rondelez, E., BAERE, I. D., Derua, R., Waelkens, E., Goris, J., et al. (2004) · Biochemical Journal · doi:10.1042/bj20031643 · Cited by 101 · see citing works
Leulliot, N., Quevillon‐Chéruel, S., Sorel, I., de la Sierra-Gallay, I. L., Collinet, B., Graille, M., Blondeau, K., Bettache, N., Anne Poupon, B., Janin, J., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311484200 · Cited by 86 · see citing works
In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors
Sarno, P. D., Bijur, G. N., Zmijewska, A. A., Li, X., & Jope, R. S. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.03.003 · Cited by 81 · see citing works
Self-citationSontag, J., Nunbhakdi‐Craig, V., Montgomery, L. G., Arning, E., Bottiglieri, T., & Sontag, E. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2816-08.2008 · Cited by 77 · see citing works
Li, X.-C., Lu, F., Tian, Q., Yang, Y., Wang, Q., & Wang, J.-H. (2005) · Journal of neural transmission · doi:10.1007/s00702-005-0303-7 · Cited by 70 · see citing works
Self-citationMartin, L., Page, G., & Terro, F. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.05.010 · Cited by 65 · see citing works
Gong, C., Wang, J., Iqbal, K., & Grundke, I. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(03)00096-x · Cited by 64 · see citing works
Clavaguera, F., Grueninger, F., & Tolnay, M. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.08.037 · Cited by 60 · see citing works
Tian, Q., Lin, Z.-Q., Wang, X., Chen, J., Wang, Q., Gong, C., & Wang, J. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.03.037 · Cited by 57 · see citing works
Self-citationZhao, L.-H., Ding, Y., Zhang, L., & Li, L. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.08.016 · Cited by 57 · see citing works
Self-citationHwang, J., Lee, J. A., & Pallas, D. C. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.739920 · Cited by 56 · see citing works
Regulation of protein phosphatase 2A (PP2A) tumor suppressor function by PME-1
Kaur, A., & Westermarck, J. K. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160161 · Cited by 53 · see citing works
Garcia, L., Garcia, F., Llorens, F., Unzeta, M., Itarte, E., & Gómez, N. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02950-2 · Cited by 48 · see citing works
Immunological memory to hyperphosphorylated tau in asymptomatic individuals
Pascual, G., Wadia, J. S., Zhu, X., Keogh, E. A., Kaletaş, B. K., van Ameijde, J., Inganäs, H., Siregar, B., Perdok, G. J., Diefenbach, O., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1705-y · Cited by 44 · see citing works
Self-citationTakashima, A. (2012) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2012.00047 · Cited by 38 · see citing works
Yao, X., Li, X., Zhang, X., Yin, Y., Liu, B., Luo, D., Wang, Q., Wang, J., & Liu, G. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.06.018 · Cited by 37 · see citing works
Self-citationJeong, H.-C., Park, S.-J., Choi, J.-J., Go, Y., Hong, S.-K., Kwon, O.-S., Shin, J.-G., Kim, R., Lee, M.-O., Lee, S.-J., et al. (2017) · Stem Cells · doi:10.1002/stem.2642 · Cited by 35 · see citing works
Kalhor, H. R., Luk, K., Ramos, A., Zobel-Thropp, P. A., & Clarke, S. G. (2001) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2001.2558 · Cited by 29 · see citing works
Okadaic acid is taken-up into the cells mediated by human hepatocytes transporter OATP1B3
Ikema, S., Takumi, S., Maeda, Y., et al. (2015) · Food and Chemical Toxicology · doi:10.1016/j.fct.2015.06.006 · Cited by 23 · see citing works
Cornel Iridoid Glycoside Attenuates Tau Hyperphosphorylation by Inhibition of PP2A Demethylation
Yang, C., Kuai, X.-X., Li, Y., Zhang, L., Yu, J., Li, L., & Zhang, L. (2013) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2013/108486 · Cited by 23 · see citing works
Self-citationTian-chao, Y., & Lin, W. (2016) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2016.08.059 · Cited by 20 · see citing works
Ma, D., Zhu, Y., Li, Y., Yang, C., Zhang, L., Li, Y., Li, L., & Zhang, L. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.06.008 · Cited by 18 · see citing works
Self-citationRanjan, P., & Heintz, N. H. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.08.049 · Cited by 17 · see citing works
Jiang, Z., Li, Y., Jiang, L., et al. (2013) · PubMed · Cited by 17 · see citing works
Self-citationInhibition of Protein Phosphatase 2A: Focus on the Glutamatergic System
Zimmer, E. R., Leuzy, A., Souza, D. O., & Portela, L. V. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9321-0 · Cited by 10 · see citing works
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Research works printed but not linked: 1
- Zhang Y. Qiao Z. L. Guo L. (2012). Clinical research of senile vascular dementia treated with Bushen Yizhi Decoction. World J. Integr. Tradit. West. Med. 7 594– 598. 10.1093/jnen/63.4.287 · DOI · Paper page
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Wang, L., Bharti, Kumar, R., Pavlov, P. F., & Winblad, B. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112915 · Cited by 92 · see citing works
Yang, J., Zhi, W., & Wang, L. (2024) · Molecules · doi:10.3390/molecules29122812 · Cited by 63 · see citing works
“These results suggest that CIG may be a promising therapeutic agent for AD treatment [184].”
Background
- Authors
- Yang, C., Li, X., Gao, W., Wang, Q., Zhang, L., Li, Y., Li, L., & Zhang, L.
- Affiliations
- Capital Medical University (CN)
- Guangzhou University of Chinese Medicine (CN)
- Corresponding author
- Li, Lin
- Zhang, Lan
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2018-06-26
- Volume
- 9
- Pages
- 682-682
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC6028923
- OpenAlex
- W2809901315
- Cited by
- 36
- References
- 59
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 10 · 2021: 2 · 2020: 8 · 2019: 3
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81473373, 81703729, 81673406)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- tau hyperphosphorylation, GSK3β, protein phosphatase 2A, PI3K/Akt signaling, neurofibrillary pathology, Alzheimer's disease, Cornus officinalis
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