Geniposide Attenuates the Phosphorylation of Tau Protein in Cellular and Insulin‐deficient APP/PS1 Transgenic Mouse Model of Alzheimer's Disease
Abstract
Our previous studies have shown that geniposide plays an essential role in glucose‐stimulated insulin secretion from pancreatic β cells and also regulates the metabolism of Aβ and its deposition in neurons. In this study, we reported that insulin deficiency induced significant increase of tau phosphorylation. Administration of geniposide for 4 weeks significantly decreased the phosphorylated level of tau and the acceleration of GSK‐3β phosphorylation in the brain of APP/PS1 transgenic mice induced by insulin deficiency. We also observed that geniposide decreased the phosphorylation of tau protein directly and increased the phosphorylation of Akt in primary cultured cortical neurons. Furthermore, geniposide enhanced the role of insulin on the phosphorylation of Akt, GSK‐3β, and tau in primary cultured cortical neurons. And these effects of geniposide in cortical neurons could be prevented by preincubation with LY294002, an inhibitor of PI3K. Taken together, our findings provide a mechanistic and perhaps a foundational link between diabetes and Alzheimer's disease and are consistent with the notion that geniposide might play an essential role on the phosphorylation of tau protein via enhancing insulin signaling and may convey a therapeutic benefit in Alzheimer's disease.
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High fat diet is thought to contribute directly to several key aspects of AD, including increased accumulation of Aβ, tau hyperphosphorylation, and inflammation of peripheral organs and brain.
“High fat diet is thought to contribute directly to several key aspects of AD, including increased accumulation of Aβ, tau hyperphosphorylation, and inflammation of peripheral organs and brain [595–597].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [597]
Cites
Ten years of protein kinase B signalling: a hard Akt to follow
Brazil, D. P., & Hemmings, B. A. (2001) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(01)01958-2 · Cited by 1,177 · see citing works
Insulin and Insulin-like Growth Factor-1 Regulate Tau Phosphorylation in Cultured Human Neurons*
Hong, M., & Lee, V. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.31.19547 · Cited by 533 · see citing works
Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes
Liu, Y. M., Liu, F., Grundke, I., Iqbal, K., & Gong, C. (2011) · The Journal of Pathology · doi:10.1002/path.2912 · Cited by 505 · see citing works
Glycogen synthase kinase 3: an emerging therapeutic target
Eldar-Finkelman, H. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(01)02266-3 · Cited by 405 · see citing works
Grünblatt, E., Šalković‐Petrišić, M., Barilar, J. O., Riederer, P. F., & Hoyer, S. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04368.x · Cited by 376 · see citing works
Does insulin dysfunction play a role in Alzheimer's disease?
Gasparini, L. (2002) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(02)02037-0 · Cited by 314 · see citing works
Reddy, P. H. (2011) · Brain Research · doi:10.1016/j.brainres.2011.07.052 · Cited by 300 · see citing works
Temporal memory deficits in Alzheimer’s mouse models: Rescue by genetic deletion of BACE1
Ohno, M., Chang, L., Tseng, W., Oakley, H., Citron, M., Klein, W. L., Vassar, R., & Disterhoft, J. F. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04551.x · Cited by 298 · see citing works
Neill, C. O. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2013.02.025 · Cited by 292 · see citing works
Jolivalt, C. G., Lee, C. A., Beiswenger, K., Smith, J., Orlov, M., Torrance, M., & Masliah, E. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21787 · Cited by 281 · see citing works
Biessels, G. J., & Kappelle, L. J. (2005) · Biochemical Society Transactions · doi:10.1042/bst0331041 · Cited by 266 · see citing works
Insulin Resistance and Alzheimers Disease: Molecular Links & Clinical Implications
Neumann, K., Rojo, L., Navarrete, L., Farias, G., Reyes, P., & Maccioni, R. (2008) · Current Alzheimer Research · doi:10.2174/156720508785908919 · Cited by 236 · see citing works
Tau Cleavage and Dephosphorylation in Cerebellar Granule Neurons Undergoing Apoptosis
Canu, N., Dus, L., Barbato, C., Ciotti, M. T., Brancolini, C., Rinaldi, A. M., Novak, M., Cattaneo, A., Bradbury, A., & Calissano, P. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-18-07061.1998 · Cited by 232 · see citing works
Šalković‐Petrišić, M., Tribl, F., Schmidt, M., Hoyer, S., & Riederer, P. F. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03637.x · Cited by 223 · see citing works
Sayas, C. L., Moreno-Flores, M. T., Ávila, J., & Wandosell, F. G. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.52.37046 · Cited by 172 · see citing works
Gengler, S., Hamilton, A., & Hölscher, C. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009764 · Cited by 166 · see citing works
Devi, L., Alldred, M. J., Ginsberg, S. D., & Ohno, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032792 · Cited by 155 · see citing works
Liu, J., Yin, F., Zheng, X., Jing, J., & Hu, Y. (2007) · Neurochemistry International · doi:10.1016/j.neuint.2007.04.021 · Cited by 145 · see citing works
Self-citationPeripheral Hyperinsulinemia Promotes Tau Phosphorylation In Vivo
Freude, S., Plum, L., Schnitker, J., Leeser, U., Udelhoven, M., Krone, W., Brüning, J. C., & Schubert, M. (2005) · Diabetes · doi:10.2337/diabetes.54.12.3343 · Cited by 144 · see citing works
Gao, C., Liu, Y., Jiang, Y., Ding, J., & Li, L. (2013) · Brain Pathology · doi:10.1111/bpa.12116 · Cited by 141 · see citing works
Hepatoprotective effects of geniposide in a rat model of nonalcoholic steatohepatitis
Ma, T., Huang, C., Zong, G., Zha, D., Meng, X., Li, J., & Tang, W. (2011) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.2011.01256.x · Cited by 107 · see citing works
Song, X., Zhang, W., Wang, T., Jiang, H., Zhang, Z., Fu, Y., Yang, Z., Cao, Y., & Zhang, N. (2014) · Inflammation · doi:10.1007/s10753-014-9885-2 · Cited by 103 · see citing works
Kojima, K., Shimada, T., Nagareda, Y., Watanabe, M., Ishizaki, J., Sai, Y., Miyamoto, K., & Aburada, M. (2011) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.34.1613 · Cited by 101 · see citing works
Failures to reconsolidate memory in a mouse model of Alzheimer’s disease
Ohno, M. (2009) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2009.05.001 · Cited by 95 · see citing works
Meske, V., Albert, F., & Ohm, T. G. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704292200 · Cited by 94 · see citing works
Xiong, H., Chen, Z., Wang, J., Song, J., Zhao, G., Shen, H., & Deng, Y. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130584 · Cited by 90 · see citing works
Hiltunen, M. O., Khandelwal, V. K. M., Yaluri, N., Tiilikainen, T., Tusa, M., Koivisto, H., Krzisch, M., Vepsäläinen, S., Mäkinen, P. M., Kemppainen, S., et al. (2011) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2011.01384.x · Cited by 72 · see citing works
The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse
Schechter, R., Beju, D., & Miller, K. E. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.07.001 · Cited by 61 · see citing works
Ponce-López, T., Liy-Salmerón, G., Hong, E., & Meneses, A. (2011) · Brain Research · doi:10.1016/j.brainres.2011.09.056 · Cited by 59 · see citing works
Alzheimer's Disease and Diabetes: New Insights and Unifying Therapies
Vignini, A., Giulietti, A., Nanetti, L., Raffaelli, F., Giusti, L., Mazzanti, L., & Provinciali, L. (2013) · Current Diabetes Reviews · doi:10.2174/1573399811309030003 · Cited by 57 · see citing works
Deutsch, S. I., Rosse, R. B., & Lakshman, M. (2006) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2006.04.007 · Cited by 56 · see citing works
Geniposide Attenuates Mitochondrial Dysfunction and Memory Deficits in APP/PS1 Transgenic Mice
Lv, C., Liu, X., Liu, H., Chen, T., & Zhang, W. (2014) · Current Alzheimer Research · doi:10.2174/1567205011666140618095925 · Cited by 49 · see citing works
Negishi, T., Ishii, Y., Kyuwa, S., Kuroda, Y., & Yoshikawa, Y. (2003) · Neuroscience Letters · doi:10.1016/j.neulet.2003.09.031 · Cited by 42 · see citing works
Progress in the development of new drugs in Alzheimer's disease
Piau, A., Nourhashémi, F., Hein, C., Caillaud, C., & Vellas, B. J. (2011) · The journal of nutrition health & aging · doi:10.1007/s12603-011-0012-x · Cited by 41 · see citing works
Lv, C., Wang, L., Liu, X., Cong, X., Yan, S. S., Wang, Y., & Zhang, W. (2014) · Current Alzheimer Research · doi:10.2174/1567205011666140514111204 · Cited by 34 · see citing works
Geniposide decreases the level of Aβ1−42 in the hippocampus of streptozotocin-induced diabetic rats
Liu, J., Zhang, Y., Deng, X., & Yin, F. (2013) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmt069 · Cited by 32 · see citing works
Self-citationYin, F., Zhang, Y., Guo, L., Kong, S., & Liu, J. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527311211080015 · Cited by 28 · see citing works
Self-citationFighting Alzheimer's Disease and Type 2 Diabetes: Pathological links and Treatment Strategies
Dai, Y., & Kamal, M. A. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/18715273113126660134 · Cited by 26 · see citing works
The Role of Neurotrophins and Insulin on Tau Pathology in Alzheimer's Disease
Elliott, E., & Ginzburg, I. (2006) · Reviews in the Neurosciences · doi:10.1515/revneuro.2006.17.6.635 · Cited by 23 · see citing works
Delobel, P., Flament, S., Hamdane, M., Delacourte, A., Vilain, J., & Buée, L. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02525-5 · Cited by 22 · see citing works
Insulin resistance: an emerging link in Alzheimer’s disease
Medhi, B., & Chakrabarty, M. (2013) · Neurological Sciences · doi:10.1007/s10072-013-1454-1 · Cited by 21 · see citing works
Simón, D., Medina, M., Ávila, J., & Wandosell, F. G. (2011) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152711794480401 · Cited by 16 · see citing works
Alzheimer’s disease risk, obesity and tau: is insulin resistance guilty?
Blum, D. L., & Buée, L. (2013) · Expert Review of Neurotherapeutics · doi:10.1586/ern.13.35 · Cited by 8 · see citing works
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Walker, J. M., Dixit, S., Saulsberry, A. C., May, J. M., & Harrison, F. E. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.01.004 · Cited by 110 · see citing works
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Zhou, Y., Zhang, R., Rahman, K., Cao, Z., Zhang, H., & Peng, C. (2019) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2019/4925682 · Cited by 97 · see citing works
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Zhao, J., Wei, M., Guo, M., Wang, M., Niu, H., Xu, T., & Zhou, Y. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14818 · Cited by 97 · see citing works
Bracko, O., Vinarcsik, L. K., Cruz Hernández, J. C., Ruiz-Uribe, N. E., Haft-Javaherian, M., Falkenhain, K., Ramanauskaite, E. M., Ali, M., Mohapatra, A., Swallow, M. A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-65908-y · Cited by 85 · see citing works
Deng, R., Wu, H., Yan, W., & Mengdie, W. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.113958 · Cited by 69 · see citing works
Zhou, Z., Hou, J., Mo, Y., Ren, M., Yang, G., Qu, Z., & Hu, Y. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172857 · Cited by 66 · see citing works
Wang, Y., Hu, H., Liu, X., & Guo, X. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1138499 · Cited by 67 · see citing works
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Huang, C., Chu, H., Ma, Y., Zhou, Z., Dai, C., Huang, X., Fang, L., Ao, Q., & Huang, D. (2018) · Brain stimulation · doi:10.1016/j.brs.2018.08.015 · Cited by 50 · see citing works
The emerging possibility of the use of geniposide in the treatment of cerebral diseases: a review
Zhang, W., Zhang, F., Hu, Q., Xiao, X., Ou, L., Chen, Y., Luo, S., Cheng, Y., Jiang, Y., Ma, X., et al. (2021) · Chinese Medicine · doi:10.1186/s13020-021-00486-3 · Cited by 46 · see citing works
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Yan, L., Pan, H., Zhang, X., Wang, H., Liu, S., Zhang, H., Qian, H., Wang, L., & Ying, H. (2019) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.9b00402 · Cited by 36 · see citing works
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- Authors
- Zhang, Y., Yin, F., Liu, J., & Liu, Z.
- Affiliations
- Chongqing University of Technology (CN)
- Chongqing Technology and Business University (CN)
- Corresponding author
- Yin, Fei
- Venue
- Chemical Biology & Drug Design
- Publisher
- Wiley
- Published
- 2015-11-12
- Volume
- 87
- Issue
- 3
- Pages
- 409-418
- ISSN
- 1747-0277 (ISSN-L)
- 1747-0285
- OpenAlex
- W2106039436
- Cited by
- 34
- References
- 43
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 3 · 2021: 4 · 2020: 2 · 2019: 5 · 2018: 6 · 2017: 4 · 2016: 2
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Chemical Biology & Drug Design (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81173063)
- Chongqing Science and Technology Commission (2014jcyjjq10003, 2013jjb10032)
- 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 › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
- Keywords
- geniposide, tau phosphorylation, insulin deficiency, Alzheimer's disease, APP/PS1 mice, GSK3β, Akt phosphorylation, insulin signaling, phosphatidylinositol 3-kinase, cortical neurons, diabetes mellitus, neuroprotection
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Humans, Insulin, Mice, Transgenic, Phosphorylation, Amyloid beta-Protein Precursor, tau Proteins, Iridoids, Mice, Presenilin-1
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