Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 2, pp 159–168 | Cite as

Sarsasapogenin suppresses Aβ overproduction induced by high glucose in HT-22 cells

  • Meng-Ya Zhang
  • Yu Li
  • Shen-Yuan Yin
  • Li Kong
  • Xiao-Li Liu
  • Xiao-Xing YinEmail author
  • Yao-Wu LiuEmail author
Original Article


The aim of this study is to investigate effects and potential mechanisms of sarsasapogenin (Sar), an active component purified from Rhizoma Anemarrhenae, on high glucose-induced amyloid-beta (Aβ) peptide overproduction in HT-22 cells. HT-22 cells were divided into normal glucose; high glucose (HG); HG co-treated with low, middle, and high concentration of Sar (1, 5, 25 μmol/L); and peroxisome proliferator-activated receptor γ (PPARγ) agonist (10 μmol/L pioglitazone). After treatment for 24 h, protein expression of Aβ and β-site Aβ precursor protein cleaving enzyme 1 (BACE1) and activated PPARγ level were determined by Western blot; Aβ42 levels were also measured by using both immunofluorescence and ELISA methods. BACE1 activity and mRNA level were assessed by fluorospectrophotometry and quantitative PCR, respectively. Cell viability was assayed with a CCK-8 kit. Elevated Aβ expression and Aβ42 level were found in HG-treated HT-22 cells, accompanied by increased BACE1 protein and mRNA levels as well as enzymatic activity, which was markedly attenuated by three concentrations of Sar and pioglitazone. Moreover, HG reduced nuclear PPARγ levels, which was reversed by middle and high concentrations of Sar as well as pioglitazone. PPARγ antagonist GW9662 (20 μmol/L) pretreatment reversed the effect of Sar on BACE1 protein expression in HG-cultured HT-22 cells. Additionally, Sar suppressed HG-induced decreases in cell viability of HT-22 cells. High glucose can induce an increase in Aβ levels and a decrease in cell viability in HT-22 cells, while co-treatment with Sar improves these results, which is mediated likely through activation of PPARγ and subsequent downregulation of BACE1.


Amyloid-beta peptides β-Site Aβ precursor protein cleaving enzyme 1 High glucose Peroxisome proliferator-activated receptor γ Sarsasapogenin 


Funding information

The work was supported through funding from Qing Lan Project of Jiangsu Province (2014), China, and the Priority Academic Program Development of Jiangsu Higher Education Institutions, China.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC (2001) BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 4(3):233–234. CrossRefPubMedGoogle Scholar
  2. Cai Z, Zhao Y, Yao S, Bin Zhao B (2011) Increases in beta-amyloid protein in the hippocampus caused by diabetic metabolic disorder are blocked by minocycline through inhibition of NF-kappaB pathway activation. Pharmacol Rep 63(2):381–391. CrossRefPubMedGoogle Scholar
  3. Cao G, Su P, Zhang S, Guo L, Zhang H, Liang Y, Qin C, Zhang W (2016) Ginsenoside Re reduces Abeta production by activating PPARgamma to inhibit BACE1 in N2a/APP695 cells. Eur J Pharmacol 793:101–108. CrossRefPubMedGoogle Scholar
  4. Chen LM, Lin ZY, Zhu YG, Lin N, Zhang J, Pan XD, Chen XC (2012) Ginsenoside Rg1 attenuates beta-amyloid generation via suppressing PPARgamma-regulated BACE1 activity in N2a-APP695 cells. Eur J Pharmacol 675(1-3):15–21. CrossRefPubMedGoogle Scholar
  5. Chen Q, Qia XZ, Hu YE (2002) Effects of ZMS on deposition of β-amyloid peptide and cholinergic function in rats with β-amyloid injection into right nucleus basalis magnocellularis (in Chinese). Zhong Guo Yao Li Xue Tong Bao (Chin Pharmacol Bull) 18:390–393Google Scholar
  6. Chen Y, Cao CP, Li CR, Wang W, Zhang D, Han LL, Zhang XQ, Kim A, Kim S, Liu GL (2010) Ghrelin modulates insulin sensitivity and tau phosphorylation in high glucose-induced hippocampal neurons. Biol Pharm Bull 33(7):1165–1169. CrossRefPubMedGoogle Scholar
  7. Ding H, Wang H, Zhao Y, Sun D, Zhai X (2015) Protective effects of baicalin on Abeta(1)(−)(4)(2)-induced learning and memory deficit, oxidative stress, and apoptosis in rat. Cell Mol Neurobiol 35(5):623–632. CrossRefPubMedGoogle Scholar
  8. Du J, Zhang L, Liu S, Zhang C, Huang X, Li J, Zhao N, Wang Z (2009) PPARgamma transcriptionally regulates the expression of insulin-degrading enzyme in primary neurons. Biochem Biophys Res Commun 383(4):485–490. CrossRefPubMedGoogle Scholar
  9. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 100(7):4162–4167. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, O’Banion K, Klockgether T, Van Leuven F, Landreth GE (2005) Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 128(6):1442–1453. CrossRefPubMedGoogle Scholar
  11. Higuchi M, Iwata N, Saido TC (2005) Understanding molecular mechanisms of proteolysis in Alzheimer’s disease: progress toward therapeutic interventions. Biochim Biophys Acta 1751(1):60–67. CrossRefPubMedGoogle Scholar
  12. Hong H, Liu LP, Liao JM, Wang TS, Ye FY, Wu J, Wang YY, Wang Y, Li YQ, Long Y, Xia YZ (2009) Downregulation of LRP1 [correction of LPR1] at the blood-brain barrier in streptozotocin-induced diabetic mice. Neuropharmacology 56(6-7):1054–1059. CrossRefPubMedGoogle Scholar
  13. Hu Y, Xia Z, Sun Q, Orsi A, Rees D (2005) A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Res 1060(1-2):26–39. CrossRefPubMedGoogle Scholar
  14. Huang HJ, Liang KC, Chen CP, Chen CM, Hsieh-Li HM (2007) Intrahippocampal administration of A beta(1-40) impairs spatial learning and memory in hyperglycemic mice. Neurobiol Learn Mem 87(4):483–494. CrossRefPubMedGoogle Scholar
  15. Huang JF, Shang L, Liu P, Zhang MQ, Chen S, Chen D, Fan CL, Wang H, Xiong K (2012) Timosaponin-BII inhibits the up-regulation of BACE1 induced by ferric chloride in rat retina. BMC Complement Altern Med 12:189. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62(6):925–931. CrossRefPubMedGoogle Scholar
  17. Jiang LY, Tang SS, Wang XY, Liu LP, Long Y, Hu M, Liao MX, Ding QL, Hu W, Li JC, Hong H (2012) PPARgamma agonist pioglitazone reverses memory impairment and biochemical changes in a mouse model of type 2 diabetes mellitus. CNS Neurosci Ther 18(8):659–666. CrossRefPubMedGoogle Scholar
  18. Jolivalt CG, Hurford R, Lee CA, Dumaop W, Rockenstein E, Masliah E (2010) Type 1 diabetes exaggerates features of Alzheimer’s disease in APP transgenic mice. Exp Neurol 223(2):422–431. CrossRefPubMedGoogle Scholar
  19. Kamal A, Biessels GJ, Duis SE, Gispen WH (2000) Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing. Diabetologia 43(4):500–506. CrossRefPubMedGoogle Scholar
  20. Lee B, Jung K, Kim DH (2009) Timosaponin AIII, a saponin isolated from Anemarrhena asphodeloides, ameliorates learning and memory deficits in mice. Pharmacol Biochem Behav 93(2):121–127. CrossRefPubMedGoogle Scholar
  21. Li TJ, Qiu Y, Yang PY, Rui YC, Chen WS (2007a) Timosaponin B-II improves memory and learning dysfunction induced by cerebral ischemia in rats. Neurosci Lett 421(2):147–151. CrossRefPubMedGoogle Scholar
  22. Li ZG, Zhang W, Sima AA (2007b) Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes 56(7):1817–1824. CrossRefPubMedGoogle Scholar
  23. Liu LP, Yan TH, Jiang LY, Hu W, Hu M, Wang C, Zhang Q, Long Y, Wang JQ, Li YQ, Hong H (2013) Pioglitazone ameliorates memory deficits in streptozotocin-induced diabetic mice by reducing brain beta-amyloid through PPARgamma activation. Acta Pharmacol Sin 34(4):455–463. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Liu Y, Liu H, Yang J, Liu X, Lu S, Wen T, Xie L, Wang G (2008) Increased amyloid beta-peptide (1-40) level in brain of streptozotocin-induced diabetic rats. Neuroscience 153(3):796–802. CrossRefPubMedGoogle Scholar
  25. Liu YW, Zhang L, Li Y, Cheng YQ, Zhu X, Zhang F, Yin XX (2016) Activation of mTOR signaling mediates the increased expression of AChE in high glucose condition: in vitro and in vivo evidences. Mol Neurobiol 53(7):4972–4980. CrossRefPubMedGoogle Scholar
  26. Liu YW, Zhu X, Lu Q, Wang JY, Li W, Wei YQ, Yin XX (2012) Total saponins from Rhizoma Anemarrhenae ameliorate diabetes-associated cognitive decline in rats: involvement of amyloid-beta decrease in brain. J Ethnopharmacol 139(1):194–200. CrossRefPubMedGoogle Scholar
  27. Liu YW, Zhu X, Zhang L, Lu Q, Zhang F, Guo H, Yin XX (2014) Cerebroprotective effects of ibuprofen on diabetic encephalopathy in rats. Pharmacol Biochem Behav 117:128–136. CrossRefPubMedGoogle Scholar
  28. Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R (2001) Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4(3):231–232. CrossRefPubMedGoogle Scholar
  29. Ma D, Zhang J, Sugahara K, Sagara Y, Kodama H (2001) Effect of sarsasapogenin and its derivatives on the stimulus coupled responses of human neutrophils. Clin Chim Acta 314(1-2):107–112. CrossRefPubMedGoogle Scholar
  30. Qi WW, Zhong LY, Li XR, Li G, Liu ZX, Hu JF, Chen NH (2012) Hyperglycemia induces the variations of 11beta-hydroxysteroid dehydrogenase type 1 and peroxisome proliferator-activated receptor-gamma expression in hippocampus and hypothalamus of diabetic rats. Exp Diabetes Res 2012:107130. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT (2003) Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci 23(30):9796–9804PubMedGoogle Scholar
  32. Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, Walter J, Klockgether T, van Leuven F, Heneka MT (2006) Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci U S A 103(2):443–448. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Selkoe DJ (2000) Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci 924:17–25CrossRefPubMedGoogle Scholar
  34. Sharifi AM, Mousavi SH, Farhadi M, Larijani B (2007) Study of high glucose-induced apoptosis in PC12 cells: role of bax protein. J Pharmacol Sci 104(3):258–262. CrossRefPubMedGoogle Scholar
  35. Sima AA, Li ZG (2005) The effect of C-peptide on cognitive dysfunction and hippocampal apoptosis in type 1 diabetic rats. Diabetes 54(5):1497–1505. CrossRefPubMedGoogle Scholar
  36. Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, Kurinami H, Shinohara M, Rakugi H, Morishita R (2010) Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A 107(15):7036–7041. CrossRefPubMedPubMedCentralGoogle Scholar
  37. van der Graaf M, Janssen SW, van Asten JJ, Hermus AR, Sweep CG, Pikkemaat JA, Martens GJ, Heerschap A (2004) Metabolic profile of the hippocampus of Zucker diabetic fatty rats assessed by in vivo 1H magnetic resonance spectroscopy. NMR Biomed 17(6):405–410. CrossRefPubMedGoogle Scholar
  38. Wang X, Wang Y, JP H, Yu S, Li BK, Cui Y, Ren L, Zhang LD (2017) Astragaloside IV, a natural PPARgamma agonist, reduces Abeta production in Alzheimer’s disease through inhibition of BACE1. Mol Neurobiol 54(4):2939–2949. CrossRefPubMedGoogle Scholar
  39. Wang X, Zheng W, Xie JW, Wang T, Wang SL, Teng WP, Wang ZY (2010) Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol Neurodegener 5(1):46. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Xu PX, Wang SW, XL Y, YJ S, Wang T, Zhou WW, Zhang H, Wang YJ, Liu RT (2014) Rutin improves spatial memory in Alzheimer’s disease transgenic mice by reducing Abeta oligomer level and attenuating oxidative stress and neuroinflammation. Behav Brain Res 264:173–180CrossRefPubMedGoogle Scholar
  41. Zhang R, Wang ZM, Xia ZQ, Hu YE (2008) Effects of active component of Zhimu on APP and BACE1 in HEK293sw cells (in Chinese). J Shanghai Jiaotong Univ Med Sci 28:827–830Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouChina
  2. 2.Department of Pharmacy, Affiliated Wuxi Children’s HospitalNanjing Medical UniversityWuxiChina
  3. 3.Department of Pharmacology, School of PharmacyXuzhou Medical UniversityXuzhouChina

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