首页 » 文章 » 文章详细信息
Oxidative Medicine and Cellular Longevity Volume 2021 ,2021-09-26
Depichering the Effects of Astragaloside IV on AD-Like Phenotypes: A Systematic and Experimental Investigation
Research Article
Xuncui Wang 1 Feng Gao 1 Wen Xu 2 Yin Cao 1 Jinghui Wang 3 Guoqi Zhu 1
Show affiliations
DOI:10.1155/2021/1020614
Received 2021-6-25, accepted for publication 2021-8-30, Published 2021-09-26
PDF
摘要

Astragaloside IV (AS-IV) is an active component in Astragalus membranaceus with the potential to treat neurodegenerative diseases, especially Alzheimer’s diseases (ADs). However, its mechanisms are still not known. Herein, we aimed to explore the systematic pharmacological mechanism of AS-IV for treating AD. Drug prediction, network pharmacology, and functional bioinformatics analyses were conducted. Molecular docking was applied to validate reliability of the interactions and binding affinities between AS-IV and related targets. Finally, experimental verification was carried out in AβO infusion produced AD-like phenotypes to investigate the molecular mechanisms. We found that AS-IV works through a multitarget synergistic mechanism, including inflammation, nervous system, cell proliferation, apoptosis, pyroptosis, calcium ion, and steroid. AS-IV highly interacted with PPARγ, caspase-1, GSK3Β, PSEN1, and TRPV1 after docking simulations. Meanwhile, PPARγ interacts with caspase-1, GSK3Β, PSEN1, and TRPV1. In vivo experiments showed that AβO infusion produced AD-like phenotypes in mice, including impairment of fear memory, neuronal loss, tau hyperphosphorylation, neuroinflammation, and synaptic deficits in the hippocampus. Especially, the expression of PPARγ, as well as BDNF, was also reduced in the hippocampus of AD-like mice. Conversely, AS-IV improved AβO infusion-induced memory impairment, inhibited neuronal loss and the phosphorylation of tau, and prevented the synaptic deficits. AS-IV prevented AβO infusion-induced reduction of PPARγ and BDNF. Moreover, the inhibition of PPARγ attenuated the effects of AS-IV on BDNF, neuroflammation, and pyroptosis in AD-like mice. Taken together, AS-IV could prevent AD-like phenotypes and reduce tau hyperphosphorylation, synaptic deficits, neuroinflammation, and pyroptosis, possibly via regulating PPARγ.

授权许可

Copyright © 2021 Xuncui Wang et al. 2021
https://creativecommons.org/licenses/by/4.0/

通讯作者

1. Jinghui Wang.School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230038, China, ahtcm.edu.cn.jhwang_dlut@163.com
2. Guoqi Zhu.Key Laboratory of Xin’an Medicine, Ministry of Education, Technology Center for Scientific Research, Anhui University of Chinese Medicine, Hefei 230038, China, ahtcm.edu.cn.guoqizhu@gmail.com

推荐引用方式

Xuncui Wang,Feng Gao,Wen Xu,Yin Cao,Jinghui Wang,Guoqi Zhu. Depichering the Effects of Astragaloside IV on AD-Like Phenotypes: A Systematic and Experimental Investigation. Oxidative Medicine and Cellular Longevity ,Vol.2021(2021)

您觉得这篇文章对您有帮助吗?
分享和收藏
0

是否收藏?

参考文献
[1] . DOI: 10.3389/fncel.2015.00191.
[2] V. Calsolaro, P. Edison. (2016). Neuroinflammation in Alzheimer's disease: current evidence and future directions. Alzheimers Dement.12(6):719-732. DOI: 10.3389/fncel.2015.00191.
[3] Y. Zhang, N. Q. Huang, F. Yan, H. Jin. et al.(2018). Diabetes mellitus and Alzheimer's disease: GSK-3 as a potential link. Behavioural Brain Research.339:57-65. DOI: 10.3389/fncel.2015.00191.
[4] S. Mandrekar-Colucci, A. Sauerbeck, P. G. Popovich, D. M. McTigue. et al.(2013). PPAR agonists as therapeutics for CNS trauma and neurological diseases. ASN Neuro.5(5, article e00129). DOI: 10.3389/fncel.2015.00191.
[5] M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly. et al.(1998). The peroxisome proliferator-activated receptor- is a negative regulator of macrophage activation. Nature.391(6662):79-82. DOI: 10.3389/fncel.2015.00191.
[6] X. Wang, W. Xu, H. Chen, W. Li. et al.(2020). Astragaloside IV prevents A oligomers-induced memory impairment and hippocampal cell apoptosis by promoting PPAR/BDNF signaling pathway. Brain Research.1747:147041. DOI: 10.3389/fncel.2015.00191.
[7] Y. F. Pan, X. T. Jia, E. F. Song, X. Z. Peng. et al.(2018). Astragaloside IV protects against A1-42-induced oxidative stress, neuroinflammation and cognitive impairment in rats. Chinese Medical Sciences Journal.33(1):29-37. DOI: 10.3389/fncel.2015.00191.
[8] H. Yu, J. Chen, X. Xu, Y. Li. et al.(2012). A systematic prediction of multiple drug-target interactions from chemical, genomic, and pharmacological data. PLoS One.7(5, article e37608). DOI: 10.3389/fncel.2015.00191.
[9] K. N. Green, F. M. LaFerla. (2008). Linking Calcium to A and Alzheimer's Disease. Neuron.59(2):190-194. DOI: 10.3389/fncel.2015.00191.
[10] C. Venegas, S. Kumar, B. S. Franklin, T. Dierkes. et al.(2017). Microglia-derived ASC specks cross-seed amyloid- in Alzheimer's disease. Nature.552(7685):355-361. DOI: 10.3389/fncel.2015.00191.
[11] A. Thathiah, B. de Strooper. (2009). G protein-coupled receptors, cholinergic dysfunction, and A Toxicity in Alzheimer's disease. Science Signaling.2(93):re8. DOI: 10.3389/fncel.2015.00191.
[12] X. Wang, C. Pan, J. Gong, X. Liu. et al.(2016). Enhancing the enrichment of pharmacophore-based target prediction for the polypharmacological profiles of drugs. Journal of Chemical Information and Modeling.56(6):1175-1183. DOI: 10.3389/fncel.2015.00191.
[13] S. T. Ferreira, M. V. Lourenco, M. M. Oliveira, F. G. de Felice. et al.(2015). Soluble amyloid- oligomers as synaptotoxins leading to cognitive impairment in Alzheimerâ’s disease. Frontiers in Cellular Neuroscience.9:191. DOI: 10.3389/fncel.2015.00191.
[14] X. Wang, Y. Wang, J. P. Hu, S. Yu. et al.(2017). Astragaloside IV, a natural PPAR agonist, reduces A production in Alzheimer's disease through inhibition of BACE1. Molecular Neurobiology.54(4):2939-2949. DOI: 10.3389/fncel.2015.00191.
[15] Q. Sun, N. Jia, W. Wang, H. Jin. et al.(2014). Protective effects of astragaloside IV against amyloid beta1-42 neurotoxicity by inhibiting the mitochondrial permeability transition pore opening. PLoS One.9(6, article e98866). DOI: 10.3389/fncel.2015.00191.
[16] S. Kim, I. H. Kang, J. B. Nam, Y. Cho. et al.(2015). Ameliorating the effect of astragaloside IV on learning and memory deficit after chronic cerebral hypoperfusion in rats. Molecules.20(2):1904-1921. DOI: 10.3389/fncel.2015.00191.
[17] J. Park, I. Wetzel, I. Marriott, D. Dréau. et al.(2018). A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease. Nature Neuroscience.21(7):941-951. DOI: 10.3389/fncel.2015.00191.
[18] Y. Yang, S. Kimura-Ohba, J. Thompson, G. A. Rosenberg. et al.(2016). Rodent models of vascular cognitive impairment. Translational Stroke Research.7(5):407-414. DOI: 10.3389/fncel.2015.00191.
[19] A. Daina, O. Michielin, V. Zoete. (2019). SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research.47(W1):W357-W364. DOI: 10.3389/fncel.2015.00191.
[20] M. V. Lourenco, R. L. Frozza, G. B. de Freitas, H. Zhang. et al.(2019). Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nature Medicine.25(1):165-175. DOI: 10.3389/fncel.2015.00191.
[21] S. Mostafavi, D. Ray, D. Warde-Farley, C. Grouios. et al.(2008). GeneMANIA: a real-time multiple association network integration algorithm for predicting gene function. Genome Biology.9:S4. DOI: 10.3389/fncel.2015.00191.
[22] G. Zhu, V. Briz, J. Seinfeld, Y. Liu. et al.(2017). Calpain-1 deletion impairs mGluR-dependent LTD and fear memory extinction. Scientific Reports.7(1):42788. DOI: 10.3389/fncel.2015.00191.
[23] J. Chen, Y. Chen, Y. Luo, D. Gui. et al.(2014). Astragaloside IV ameliorates diabetic nephropathy involving protection of podocytes in streptozotocin induced diabetic rats. European Journal of Pharmacology.736:86-94. DOI: 10.3389/fncel.2015.00191.
[24] R. Libro, F. Diomede, D. Scionti, A. Piattelli. et al.(2017). Cannabidiol modulates the expression of Alzheimer's disease-related genes in mesenchymal stem cells. International Journal of Molecular Sciences.18(1):26. DOI: 10.3389/fncel.2015.00191.
[25] Z. Song, F. Shen, Z. Zhang, S. Wu. et al.(2020). Calpain inhibition ameliorates depression-like behaviors by reducing inflammation and promoting synaptic protein expression in the hippocampus. Neuropharmacology.174:108175. DOI: 10.3389/fncel.2015.00191.
[26] N. A. Stefanova, K. Y. Maksimova, E. A. Rudnitskaya, N. A. Muraleva. et al.(2018). Association of cerebrovascular dysfunction with the development of Alzheimer's disease-like pathology in OXYS rats. BMC Genomics.19:75. DOI: 10.3389/fncel.2015.00191.
[27] R. G. Morris. (2006). Elements of a neurobiological theory of hippocampal function: the role of synaptic plasticity, synaptic tagging and schemas. The European Journal of Neuroscience.23(11):2829-2846. DOI: 10.3389/fncel.2015.00191.
[28] B. Lu, G. Nagappan, Y. Lu. (2014). BDNF and synaptic plasticity, cognitive function, and dysfunction. Handbook of Experimental Pharmacology.220:223-250. DOI: 10.3389/fncel.2015.00191.
[29] G. M. Morris, R. Huey, W. Lindstrom, M. F. Sanner. et al.(2009). AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. Journal of Computational Chemistry.30(16):2785-2791. DOI: 10.3389/fncel.2015.00191.
[30] Y. Chen, D. Gui, J. Chen, D. He. et al.(2014). Down-regulation of PERK-ATF4-CHOP pathway by Astragaloside IV is associated with the inhibition of endoplasmic reticulum stress-induced podocyte apoptosis in diabetic rats. Cellular Physiology and Biochemistry.33(6):1975-1987. DOI: 10.3389/fncel.2015.00191.
[31] F. Yin, H. Sancheti, I. Patil, E. Cadenas. et al.(2016). Energy metabolism and inflammation in brain aging and Alzheimer's disease. Free Radical Biology & Medicine.100:108-122. DOI: 10.3389/fncel.2015.00191.
[32] L. Mucke, E. Masliah, G. Q. Yu, M. Mallory. et al.(2000). High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. The Journal of Neuroscience.20(11):4050-4058. DOI: 10.3389/fncel.2015.00191.
[33] C. P. Figueiredo, J. R. Clarke, J. H. Ledo, F. C. Ribeiro. et al.(2013). Memantine rescues transient cognitive impairment caused by high-molecular-weight a oligomers but not the persistent impairment induced by low-molecular-weight oligomers. The Journal of Neuroscience.33(23):9626-9634. DOI: 10.3389/fncel.2015.00191.
[34] A. Mullard. (2017). Alzheimer amyloid hypothesis lives on. Nature Reviews. Drug Discovery.16(1):3-5. DOI: 10.3389/fncel.2015.00191.
[35] D. J. Selkoe. (2002). Alzheimer's disease is a synaptic failure. Science.298(5594):789-791. DOI: 10.3389/fncel.2015.00191.
[36] S. Ciudad, E. Puig, T. Botzanowski, M. Meigooni. et al.(2020). A(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage. Nature Communications.11(1):3014. DOI: 10.3389/fncel.2015.00191.
[37] R. M. Koffie, M. Meyer-Luehmann, T. Hashimoto, K. W. Adams. et al.(2009). Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proceedings of the National Academy of Sciences of the United States of America.106(10):4012-4017. DOI: 10.3389/fncel.2015.00191.
[38] J. Cummings, G. Lee, A. Ritter, M. Sabbagh. et al.(2019). Alzheimer's disease drug development pipeline: 2019. Alzheimer's & Dementia: Translational Research & Clinical Interventions.5(1):272-293. DOI: 10.3389/fncel.2015.00191.
[39] G. S. Seixas da Silva, H. M. Melo, M. V. Lourenco, N. M. Lyra e Silva. et al.(2017). Amyloid- oligomers transiently inhibit AMP-activated kinase and cause metabolic defects in hippocampal neurons. The Journal of Biological Chemistry.292(18):7395-7406. DOI: 10.3389/fncel.2015.00191.
[40] R. Cacace, K. Sleegers, C. van Broeckhoven. (2016). Molecular genetics of early-onset Alzheimer's disease revisited. Alzheimers Dement.12(6):733-748. DOI: 10.3389/fncel.2015.00191.
[41] B. Zott, M. M. Simon, W. Hong, F. Unger. et al.(2019). A vicious cycle of amyloid-dependent neuronal hyperactivation. Science.365(6453):559-565. DOI: 10.3389/fncel.2015.00191.
[42] W. Gulisano, M. Melone, C. Ripoli, M. R. Tropea. et al.(2019). Neuromodulatory action of picomolar extracellular A42 oligomers on presynaptic and postsynaptic mechanisms underlying synaptic function and memory. The Journal of Neuroscience.39(30):5986-6000. DOI: 10.3389/fncel.2015.00191.
[43] Y. Du, M. Fu, Z. Huang, X. Tian. et al.(2020). TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer's disease. Aging Cell.19(3, article e13113). DOI: 10.3389/fncel.2015.00191.
[44] J. H. Ledo, E. P. Azevedo, J. R. Clarke, F. C. Ribeiro. et al.(2013). Amyloid- oligomers link depressive-like behavior and cognitive deficits in mice. Molecular Psychiatry.18(10):1053-1054. DOI: 10.3389/fncel.2015.00191.
[45] A. Sandelius, E. Portelius, Å. Källén, H. Zetterberg. et al.(2019). Elevated CSF GAP-43 is Alzheimer's disease specific and associated with tau and amyloid pathology. Alzheimers Dement.15(1):55-64. DOI: 10.3389/fncel.2015.00191.
[46] Y. Lu, G. Xiao, W. Luo. (2017). Minocycline suppresses NLRP3 inflammasome activation in experimental ischemic stroke. Neuroimmunomodulation.23(4):230-238. DOI: 10.3389/fncel.2015.00191.
[47] P. An, J. Xie, S. Qiu, Y. Liu. et al.(2019). Hispidulin exhibits neuroprotective activities against cerebral ischemia reperfusion injury through suppressing NLRP3-mediated pyroptosis. Life Sciences.232:116599. DOI: 10.3389/fncel.2015.00191.
[48] C. Dempsey, A. Rubio Araiz, K. J. Bryson, O. Finucane. et al.(2017). Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid- and cognitive function in APP/PS1 mice. Brain, Behavior, and Immunity.61:306-316. DOI: 10.3389/fncel.2015.00191.
[49] E. L. Huttlin, R. J. Bruckner, J. A. Paulo, J. R. Cannon. et al.(2017). Architecture of the human interactome defines protein communities and disease networks. Nature.545(7655):505-509. DOI: 10.3389/fncel.2015.00191.
[50] S. J. Yang, Z. J. Song, X. C. Wang, Z. R. Zhang. et al.(2019). Curculigoside facilitates fear extinction and prevents depression-like behaviors in a mouse learned helplessness model through increasing hippocampal BDNF. Acta Pharmacologica Sinica.40(10):1269-1278. DOI: 10.3389/fncel.2015.00191.
[51] D. Puzzo, W. Gulisano, O. Arancio, A. Palmeri. et al.(2015). The keystone of Alzheimer pathogenesis might be sought in A physiology. Neuroscience.307:26-36. DOI: 10.3389/fncel.2015.00191.
[52] Y. S. Feng, Z. X. Tan, L. Y. Wu, F. Dong. et al.(2020). The involvement of NLRP3 inflammasome in the treatment of Alzheimer's disease. Ageing Research Reviews.64:101192. DOI: 10.3389/fncel.2015.00191.
[53] A. M. Pooler, M. Polydoro, E. A. Maury, S. B. Nicholls. et al.(2015). Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer's disease. Acta Neuropathologica Communications.3(1):14. DOI: 10.3389/fncel.2015.00191.
[54] K. T. Dineley, R. Kayed, V. Neugebauer, Y. Fu. et al.(2010). Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice. Journal of Neuroscience Research.88(13):2923-2932. DOI: 10.3389/fncel.2015.00191.
[55] C. Han, Y. Yang, Q. Guan, X. Zhang. et al.(2020). New mechanism of nerve injury in Alzheimer's disease: -amyloid-induced neuronal pyroptosis. Journal of Cellular and Molecular Medicine.24(14):8078-8090. DOI: 10.3389/fncel.2015.00191.
[56] S. J. Martin, P. D. Grimwood, R. G. M. Morris. (2000). Synaptic plasticity and memory: an evaluation of the hypothesis. Annual Review of Neuroscience.23(1):649-711. DOI: 10.3389/fncel.2015.00191.
[57] E. A. Miao, I. A. Leaf, P. M. Treuting, D. P. Mao. et al.(2010). Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nature Immunology.11(12):1136-1142. DOI: 10.3389/fncel.2015.00191.
[58] C. Ising, C. Venegas, S. Zhang, H. Scheiblich. et al.(2019). NLRP3 inflammasome activation drives tau pathology. Nature.575(7784):669-673. DOI: 10.3389/fncel.2015.00191.
[59] H. Guo, J. B. Callaway, J. P. Y. Ting. (2015). Inflammasomes: mechanism of action, role in disease, and therapeutics. Nature Medicine.21(7):677-687. DOI: 10.3389/fncel.2015.00191.
[60] R. A. Quintanilla, E. Utreras, F. A. Cabezas-Opazo. (2014). Role of PPAR in the Differentiation and Function of Neurons. PPAR Research.2014-9. DOI: 10.3389/fncel.2015.00191.
[61] Z. Zhang, H. Yuan, H. Zhao, B. Qi. et al.(2017). PPAR activation ameliorates postoperative cognitive decline probably through suppressing hippocampal neuroinflammation in aged mice. International Immunopharmacology.43:53-61. DOI: 10.3389/fncel.2015.00191.
[62] L. A. Denner, J. Rodriguez-Rivera, S. J. Haidacher, J. B. Jahrling. et al.(2012). Cognitive enhancement with rosiglitazone links the hippocampal PPAR and ERK MAPK signaling pathways. The Journal of Neuroscience.32(47):16725-16735. DOI: 10.3389/fncel.2015.00191.
[63] R. Gordon, E. A. Albornoz, D. C. Christie, M. R. Langley. et al.(2018). Inflammasome inhibition prevents -synuclein pathology and dopaminergic neurodegeneration in mice. Science Translational Medicine.10(465):eaah4066. DOI: 10.3389/fncel.2015.00191.
[64] A. Hiremathad, L. Piemontese. (2017). Heterocyclic compounds as key structures for the interaction with old and new targets in Alzheimer's disease therapy. Neural Regeneration Research.12(8):1256-1261. DOI: 10.3389/fncel.2015.00191.
[65] R. Kapadia, J.-H. Yi, R. Vemuganti. (2008). Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Frontiers in Bioscience.13(13):1813-1826. DOI: 10.3389/fncel.2015.00191.
文献评价指标
浏览 189次
下载全文 31次
评分次数 0次
用户评分 0.0分
分享 0次