Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside Rg1 alleviates Aβ deposition by inhibiting NADPH oxidase 2 activation in APP/PS1 mice

  • Zhang, Han (Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University) ;
  • Su, Yong (Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University) ;
  • Sun, Zhenghao (Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University) ;
  • Chen, Ming (Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University) ;
  • Han, Yuli (Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University) ;
  • Li, Yan (Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University) ;
  • Dong, Xianan (Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University) ;
  • Ding, Shixin (Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University) ;
  • Fang, Zhirui (Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University) ;
  • Li, Weiping (Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University) ;
  • Li, Weizu (Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University)
  • Received : 2020.08.08
  • Accepted : 2021.03.10
  • Published : 2021.11.15
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Abstract

Background: Ginsenoside Rg1 (Rg1), an active ingredient in ginseng, may be a potential agent for the treatment of Alzheimer's disease (AD). However, the protective effect of Rg1 on neurodegeneration in AD and its mechanism of action are still incompletely understood. Methods: Wild type (WT) and APP/PS1 AD mice, from 6 to 9 months old, were used in the experiment. The open field test (OFT) and Morris water maze (MWM) were used to detect behavioral changes. Neuronal damage was assessed by hematoxylin and eosin (H&E) and Nissl staining. Immunofluorescence, western blotting, and quantitative real-time polymerase chain reaction (q-PCR) were used to examine postsynaptic density 95 (PSD95) expression, amyloid beta (Aβ) deposition, Tau and phosphorylated Tau (p-Tau) expression, reactive oxygen species (ROS) production, and NAPDH oxidase 2 (NOX2) expression. Results: Rg1 treatment for 12 weeks significantly ameliorated cognitive impairments and neuronal damage and decreased the p-Tau level, amyloid precursor protein (APP) expression, and Aβ generation in APP/PS1 mice. Meanwhile, Rg1 treatment significantly decreased the ROS level and NOX2 expression in the hippocampus and cortex of APP/PS1 mice. Conclusions: Rg1 alleviates cognitive impairments, neuronal damage, and reduce Aβ deposition by inhibiting NOX2 activation in APP/PS1 mice.

Keywords

Acknowledgement

This study was supported by the National Natural Science Foundation of China (81671384, 81970630) and the Major projects of Anhui Provincial Department of Education (KJ2020ZD14). The authors thank Bao Li and Dake Huang in the Synthetic Laboratory of Basic Medicine College for their technical assistance.

References

  1. Zhang Z, Shen Q, Wu X, Zhang D, Xing D. Activation of PKA/SIRT1 signaling pathway by photobiomodulation therapy reduces Abeta levels in Alzheimer's disease models. Aging Cell 2020;19(1):e13054. https://doi.org/10.1111/acel.13054
  2. Kumar H, More SV, Han SD, Choi JY, Choi DK. Promising therapeutics with natural bioactive compounds for improving learning and memory-a review of randomized trials. Molecules 2012;17(9):10503-39. https://doi.org/10.3390/molecules170910503
  3. Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 2016;79(3):629-61. https://doi.org/10.1021/acs.jnatprod.5b01055
  4. Wang Y, Kan H, Yin Y, Wu W, Hu W, Wang M, et al. Protective effects of ginsenoside Rg1 on chronic restraint stress induced learning and memory impairments in male mice. Pharmacol Biochem Behav 2014;120:73-81. https://doi.org/10.1016/j.pbb.2014.02.012
  5. Fan C, Song Q, Wang P, Li Y, Yang M, Yu SY. Neuroprotective effects of ginsenoside-rg1 against depression-like behaviors via suppressing glial activation, synaptic deficits, and neuronal apoptosis in rats. Front Immunol 2018;9:2889. https://doi.org/10.3389/fimmu.2018.02889
  6. Shim JS, Song MY, Yim SV, Lee SE, Park KS. Global analysis of ginsenoside Rg1 protective effects in beta-amyloid-treated neuronal cells. J Ginseng Res 2017;41(4):566-71. https://doi.org/10.1016/j.jgr.2016.12.003
  7. Song XY, Hu JF, Chu SF, Zhang Z, Xu S, Yuan YH, et al. Ginsenoside Rg1 attenuates okadaic acid induced spatial memory impairment by the GSK3beta/ tau signaling pathway and the Abeta formation prevention in rats. Eur J Pharmacol 2013;710(1-3):29-38. https://doi.org/10.1016/j.ejphar.2013.03.051
  8. Xu TZ, Shen XY, Sun LL, Chen YL, Zhang BQ, Huang DK, et al. Ginsenoside Rg1 protects against H2O2induced neuronal damage due to inhibition of the NLRP1 inflammasome signalling pathway in hippocampal neurons in vitro. Int J Mol Med 2019;43(2):717-26.
  9. Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 2019;20(3):148-60. https://doi.org/10.1038/s41583-019-0132-6
  10. Ma MW, Wang J, Zhang Q, Wang R, Dhandapani KM, Vadlamudi RK, et al. NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener 2017;12(1):7. https://doi.org/10.1186/s13024-017-0150-7
  11. Park KW, Baik HH, Jin BK. IL-13-induced oxidative stress via microglial NADPH oxidase contributes to death of hippocampal neurons in vivo. J Immunol 2009;183(7):4666-74. https://doi.org/10.4049/jimmunol.0803392
  12. Fan LM, Geng L, Cahill-Smith S, Liu F, Douglas G, McKenzie CA, et al. Nox2 contributes to age-related oxidative damage to neurons and the cerebral vasculature. J Clin Invest 2019;129(8):3374-86. https://doi.org/10.1172/jci125173
  13. Xu T, Sun L, Shen X, Chen Y, Yin Y, Zhang J, et al. NADPH oxidase 2-mediated NLRP1 inflammasome activation involves in neuronal senescence in hippocampal neurons in vitro. Int Immunopharmacol 2019;69:60-70. https://doi.org/10.1016/j.intimp.2019.01.025
  14. Li J, Yang JY, Yao XC, Xue X, Zhang QC, Wang XX, et al. Oligomeric Abeta-induced microglial activation is possibly mediated by NADPH oxidase. Neurochem Res 2013;38(2):443-52. https://doi.org/10.1007/s11064-012-0939-2
  15. Qiu LL, Luo D, Zhang H, Shi YS, Li YJ, Wu D, et al. Nox-2-Mediated phenotype loss of hippocampal parvalbumin interneurons might contribute to postoperative cognitive decline in aging mice. Front Aging Neurosci 2016;8:234.
  16. Hu W, Zhang Y, Wu W, Yin Y, Huang D, Wang Y, et al. Chronic glucocorticoids exposure enhances neurodegeneration in the frontal cortex and hippocampus via NLRP-1 inflammasome activation in male mice. Brain Behav Immun 2016;52:58-70. https://doi.org/10.1016/j.bbi.2015.09.019
  17. Hu YD, Pang W, He CC, Lu H, Liu W, Wang ZY, et al. The cognitive impairment induced by zinc deficiency in rats aged 0 approximately 2 months related to BDNF DNA methylation changes in the hippocampus. Nutr Neurosci 2017;20(9):519-25. https://doi.org/10.1080/1028415X.2016.1194554
  18. Zhang B, Zhang Y, Wu W, Xu T, Yin Y, Zhang J, et al. Chronic glucocorticoid exposure activates BK-NLRP1 signal involving in hippocampal neuron damage. J Neuroinflammation 2017;14(1):139. https://doi.org/10.1186/s12974-017-0911-9
  19. Dong W, Cheng S, Huang F, Fan W, Chen Y, Shi H, et al. Mitochondrial dysfunction in long-term neuronal cultures mimics changes with aging. Med Sci Monit 2011;17(4). BR91-B96. https://doi.org/10.12659/MSM.881706
  20. Steeland S, Gorle N, Vandendriessche C, Balusu S, Brkic M, Van Cauwenberghe C, et al. Counteracting the effects of TNF receptor-1 has therapeutic potential in Alzheimer's disease. EMBO Mol Med 2018;10(4).
  21. Zhao J, Li K, Wan K, Sun T, Zheng N, Zhu F, et al. Organoplatinum-substituted polyoxometalate inhibits beta-amyloid aggregation for Alzheimer's therapy. Angew Chem Int Ed Engl 2019;58(50):18032-9. https://doi.org/10.1002/anie.201910521
  22. Baldeiras I, Santana I, Proenca MT, Garrucho MH, Pascoal R, Rodrigues A, et al. Oxidative damage and progression to Alzheimer's disease in patients with mild cognitive impairment. J Alzheimers Dis 2010;21(4):1165-77. https://doi.org/10.3233/JAD-2010-091723
  23. Calsolaro V, Edison P. Neuroinflammation in Alzheimer's disease: current evidence and future directions. Alzheimers Dement 2016;12(6):719-32. https://doi.org/10.1016/j.jalz.2016.02.010
  24. Li XY, Men WW, Zhu H, Lei JF, Zuo FX, Wang ZJ, et al. Age- and brain region-specific changes of glucose metabolic disorder, learning, and memory dysfunction in early Alzheimer's disease assessed in APP/PS1 transgenic mice using (18)F-FDG-PET. Int J Mol Sci 2016;17(10).
  25. Izco M, Martinez P, Corrales A, Fandos N, Garcia S, Insua D, et al. Changes in the brain and plasma Abeta peptide levels with age and its relationship with cognitive impairment in the APPswe/PS1dE9 mouse model of Alzheimer's disease. Neuroscience 2014;263:269-79. https://doi.org/10.1016/j.neuroscience.2014.01.003
  26. Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep 2006;7(9):940-6. https://doi.org/10.1038/sj.embor.7400784
  27. Volianskis A, Kostner R, Molgaard M, Hass S, Jensen MS. Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1deltaE9-deleted transgenic mice model of ss-amyloidosis. Neurobiol Aging 2010;31(7):1173-87. https://doi.org/10.1016/j.neurobiolaging.2008.08.005
  28. Blanch M, Mosquera JL, Ansoleaga B, Ferrer I, Barrachina M. Altered mitochondrial DNA methylation pattern in alzheimer disease-related pathology and in Parkinson disease. Am J Pathol 2016;186(2):385-97. https://doi.org/10.1016/j.ajpath.2015.10.004
  29. Pan Y, Short JL, Newman SA, Choy KHC, Tiwari D, Yap C, et al. Cognitive benefits of lithium chloride in APP/PS1 mice are associated with enhanced brain clearance of beta-amyloid. Brain Behav Immun 2018;70:36-47. https://doi.org/10.1016/j.bbi.2018.03.007
  30. Pietrzak RH, Lim YY, Neumeister A, Ames D, Ellis KA, Harrington K, et al. Amyloid-beta, anxiety, and cognitive decline in preclinical Alzheimer disease: a multicenter, prospective cohort study. JAMA Psychiatry 2015;72(3):284-91. https://doi.org/10.1001/jamapsychiatry.2014.2476
  31. Pereda D, Al-Osta I, Okorocha AE, Easton A, Hartell NA. Changes in presynaptic calcium signalling accompany age-related deficits in hippocampal LTP and cognitive impairment. Aging Cell 2019;18(5):e13008. https://doi.org/10.1111/acel.13008
  32. Harris JA, Devidze N, Verret L, Ho K, Halabisky B, Thwin MT, et al. Trans-synaptic progression of amyloid-beta-induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron 2010;68(3):428-41. https://doi.org/10.1016/j.neuron.2010.10.020
  33. Meyer D, Bonhoeffer T, Scheuss V. Balance and stability of synaptic structures during synaptic plasticity. Neuron 2014;82(2):430-43. https://doi.org/10.1016/j.neuron.2014.02.031
  34. Cui YQ, Wang Q, Zhang DM, Wang JY, Xiao B, Zheng Y, et al. Triptolide rescues spatial memory deficits and amyloid-beta aggregation accompanied by inhibition of inflammatory responses and MAPKs activity in APP/PS1 transgenic mice. Curr Alzheimer Res 2016;13(3):288-96. https://doi.org/10.2174/156720501303160217122803
  35. Xu YJ, Mei Y, Qu ZL, Zhang SJ, Zhao W, Fang JS, et al. Ligustilide ameliorates memory deficiency in APP/PS1 transgenic mice via restoring mitochondrial dysfunction. Biomed Res Int 2018;2018:4606752. https://doi.org/10.1155/2018/4606752
  36. Seubert P, Oltersdorf T, Lee MG, Barbour R, Blomquist C, Davis DL, et al. Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature 1993;361(6409):260-3. https://doi.org/10.1038/361260a0
  37. Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, et al. Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci U S A 1999;96(7):3922-7. https://doi.org/10.1073/pnas.96.7.3922
  38. Tiribuzi R, Crispoltoni L, Chiurchiu V, Casella A, Montecchiani C, Del Pino AM, et al. Trans-crocetin improves amyloid-beta degradation in monocytes from Alzheimer's Disease patients. J Neurol Sci 2017;372:408-12. https://doi.org/10.1016/j.jns.2016.11.004
  39. Butterfield DA, Swomley AM, Sultana R. Amyloid beta-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid Redox Signal 2013;19(8):823-35. https://doi.org/10.1089/ars.2012.5027
  40. Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, et al. Inflammatory components in human Alzheimer's disease and after active amyloid-beta42 immunization. Brain 2013;136(Pt 9):2677-96. https://doi.org/10.1093/brain/awt210
  41. Tayler H, Fraser T, Miners JS, Kehoe PG, Love S. Oxidative balance in Alzheimer's disease: relationship to APOE, Braak tangle stage, and the concentrations of soluble and insoluble amyloid-beta. J Alzheimers Dis 2010;22(4):1363-73.
  42. Qin YY, Li M, Feng X, Wang J, Cao L, Shen XK, et al. Combined NADPH and the NOX inhibitor apocynin provides greater anti-inflammatory and neuroprotective effects in a mouse model of stroke. Free Radic Biol Med 2017;104:333-45. https://doi.org/10.1016/j.freeradbiomed.2017.01.034
  43. Masamune A, Watanabe T, Kikuta K, Satoh K, Shimosegawa T. NADPH oxidase plays a crucial role in the activation of pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2008;294(1):G99-108. https://doi.org/10.1152/ajpgi.00272.2007
  44. Ansari MA, Scheff SW. NADPH-oxidase activation and cognition in Alzheimer disease progression. Free Radic Biol Med 2011;51(1):171-8. https://doi.org/10.1016/j.freeradbiomed.2011.03.025
  45. Yu H, Fan C, Yang L, Yu S, Song Q, Wang P, et al. Ginsenoside Rg1 prevents chronic stress-induced depression-like behaviors and neuronal structural plasticity in rats. Cell Physiol Biochem 2018;48(6):2470-82. https://doi.org/10.1159/000492684
  46. Zheng T, Jiang H, Jin R, Zhao Y, Bai Y, Xu H, et al. Ginsenoside Rg1 attenuates protein aggregation and inflammatory response following cerebral ischemia and reperfusion injury. Eur J Pharmacol 2019;853:65-73. https://doi.org/10.1016/j.ejphar.2019.02.018
  47. Bae HJ, Kim J, Jeon SJ, Kim J, Goo N, Jeong Y, et al. Green tea extract containing enhanced levels of epimerized catechins attenuates scopolamine-induced memory impairment in mice. J Ethnopharmacol 2020;258:112923. https://doi.org/10.1016/j.jep.2020.112923
  48. Chen T, Yang Y, Zhu S, Lu Y, Zhu L, Wang Y, et al. Inhibition of Abeta aggregates in Alzheimer's disease by epigallocatechin and epicatechin-3-gallate from green tea. Bioorg Chem 2020;105:104382. https://doi.org/10.1016/j.bioorg.2020.104382
  49. Kim SU, de Vellis J. Microglia in health and disease. J Neurosci Res 2005;81(3):302-13. https://doi.org/10.1002/jnr.20562