A Novel Compound YS-5-23 Exhibits Neuroprotective Effect by Reducing β-Site Amyloid Precursor Protein Cleaving Enzyme 1’s Expression and H2O2-Induced Cytotoxicity in SH-SY5Y Cells


The abnormally accumulated amyloid-β (Aβ) and oxidative stress contribute to the initiation and progression of Alzheimer’s disease (AD). β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for the production of Aβ. Furthermore, Aβ was reported to increase oxidative stress; then the overproduced oxidative stress continues to increase the expression and activity of BACE1. Consequently, inhibition of both BACE1 and oxidative stress is a better strategy for AD therapy compared with those one-target treatment methods. In the present study, our novel small molecule YS-5-23 was proved to possess both of the activities. Specifically, we found that YS-5-23 reduces BACE1’s expression in both SH-SY5Y and Swedish mutated amyloid precursor protein (APP) overexpressed HEK293 cells, and it can also suppress BACE1’s expression induced by H2O2. Moreover, YS-5-23 decreases H2O2-induced cytotoxicity including alleviating H2O2-induced apoptosis and loss of mitochondria membrane potential (MMP) because it attenuates the reactive oxygen species (ROS) level elevated by H2O2. Meanwhile, PI3K/Akt signaling pathway is involved in the anti-H2O2 and BACE1 inhibition effect of YS-5-23. Our findings indicate that YS-5-23 may develop as a drug candidate in the prevention and treatment of AD.

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Alzheimer's disease




Amyloid precursor protein


β-Site amyloid precursor protein cleaving enzyme 1


Reactive oxygen species

H2O2 :

Hydrogen peroxide




P-hydroxy-cinnamic acid




Mitochondria membrane potential




Superoxide dismutase


Phosphoinositide 3-kinase


Glycogen synthase kinase-3β


CAMP response element-binding protein


  1. 1.

    Ross C, Taylor M et al (2018) Liposome delivery systems for the treatment of Alzheimer's disease. Int J Nanomed 13:8507–8522. https://doi.org/10.2147/IJN.S183117

    CAS  Article  Google Scholar 

  2. 2.

    Yan R (2016) Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Transl Neurodegener 5:1–11. https://doi.org/10.1186/s40035-016-0061-5

    CAS  Article  Google Scholar 

  3. 3.

    Vassar R (2014) BACE1 inhibitor drugs in clinacal trials for Alzheimer's disease. Alzheimer's Res Ther 6:1–14. https://doi.org/10.1186/s13195-014-0089-7

    CAS  Article  Google Scholar 

  4. 4.

    McDade ERJB (2017) Stop Alzheimer's before it starts. Nature 547:153–155. https://doi.org/10.1038/547153a

    CAS  Article  Google Scholar 

  5. 5.

    Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer's disease at years. EMBO Mol Med 8:595–608. https://doi.org/10.15252/emmm.201606210

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Mullard A (2016) Alzheimer amyloid hypothesis lives on. Nat Rev Drug Discov 16:3–5. https://doi.org/10.1038/nrd.2016.281

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Cai H, Wang Y, McCarthy D, Wen H (2001) BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat Neurosci 4:233–234. https://doi.org/10.1038/85064

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Wang H, Li R, Shen Y (2013) beta-Secretase: its biology as a therapeutic target in diseases. Trends Pharmacol Sci 34:215–225. https://doi.org/10.1016/j.tips.2013.01.008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776. https://doi.org/10.1126/science.284.5415.770

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Vassar RPCK (2011) The β-secretase enzyme BACE1 as a therapeutic target for Alzheimer’s disease. Alzheimer's Res Ther 3:1–6. https://doi.org/10.1186/alzrt82

    CAS  Article  Google Scholar 

  11. 11.

    Egan MF, Kost J, Tariot PN et al (2018) Randomized trial of verubecestat for mild-to-moderate Alzheimer's disease. N Engl J Med 378:1691–1703. https://doi.org/10.1056/NEJMoa1706441

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Yang S, Liu W, Lu S, Tian YZ, Wang WY, Ling TJ, Liu RT (2016) A Novel multifunctional compound Camellikaempferoside B decreases abeta production, interferes with abeta aggregation, and prohibits abeta-mediated neurotoxicity and neuroinflammation. ACS Chem Neurosci 7:505–518. https://doi.org/10.1021/acschemneuro.6b00091

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Prati F, Bottegoni G, Bolognesi ML, Cavalli A (2018) BACE-1 inhibitors: from recent single-target molecules to multitarget compounds for Alzheimer's disease. J Med Chem 61:619–637. https://doi.org/10.1021/acs.jmedchem.7b00393

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Sultana R, Perluigi M, Butterfield DA (2009) Oxidatively modified proteins in Alzheimer's disease (AD), mild cognitive impairment and animal models of AD: role of Abeta in pathogenesis. Acta Neuropathol 118:1–31. https://doi.org/10.1007/s00401-009-0517-0

    CAS  Article  Google Scholar 

  15. 15.

    Zhang JDAB (2017) Oxidative stress and neurodegeneration. Brain Res Bull 133:1–3. https://doi.org/10.1016/j.brainresbull.2017.04.018

    Article  PubMed  Google Scholar 

  16. 16.

    Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L (2017) Oxidative stress in neurodegenerative diseases: from molecular mechanisms to clinical applications. Oxid Med Cell Longev 2017:1–11. https://doi.org/10.1155/2017/2525967

    CAS  Article  Google Scholar 

  17. 17.

    Zhao YBZ (2013) Oxidative stress and the pathogenesis of Alzheimer's disease. Oxid Med Cell Longev 2013:1–10. https://doi.org/10.1155/2013/316523

    CAS  Article  Google Scholar 

  18. 18.

    Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247. https://doi.org/10.1038/35041687

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Wang Y, Xu Y, Liu Q et al (2017) Myosin IIA-related actomyosin contractility mediates oxidative stress-induced neuronal apoptosis. Front Mol Neurosci 10:1–20. https://doi.org/10.3389/fnmol.2017.00075

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Gu X, Sun J, Li S, Wu X, Li L (2013) Oxidative stress induces DNA demethylation and histone acetylation in SH-SY5Y cells: potential epigenetic mechanisms in gene transcription in Abeta production. Neurobiol Aging 34:1069–1079. https://doi.org/10.1016/j.neurobiolaging.2012.10.013

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Guglielmotto M, Giliberto L, Tamagno E, Tabaton M (2010) Oxidative stress mediates the pathogenic effect of different Alzheimer's disease risk factors. Front Aging Neurosci 2:1–8. https://doi.org/10.3389/neuro.24.003.2010

    CAS  Article  Google Scholar 

  22. 22.

    Engelhart MJ, Geerlings MI, Annemieke R, Swieten JC, Van H, Albert JCM, Witteman MMBB (2002) Dietary intake of antioxidants and risk of Alzheimer disease. J Am Med Assoc 287:3223–3329. https://doi.org/10.1001/jama.287.24.3261

    CAS  Article  Google Scholar 

  23. 23.

    Dixit S, Fessel JP, Harrison FE (2017) Mitochondrial dysfunction in the APP/PSEN1 mouse model of Alzheimer's disease and a novel protective role for ascorbate. Free Radic Biol Med 112:515–523. https://doi.org/10.1016/j.freeradbiomed.2017.08.021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Kumju YJM (2012) Inhibitory effects of key compounds isolated from Corni fructus on BACE1 activity. Phytother Res 26:1714–1718. https://doi.org/10.1002/ptr.4638

    CAS  Article  Google Scholar 

  25. 25.

    Choi S-H, Hur J-M, Yang E-J et al (2008) β-secretase (BACE1) inhibitors from Perilla frutescens var. acuta. Arch Pharmacal Res 31:183–187. https://doi.org/10.1007/s12272-001-1139-9

    CAS  Article  Google Scholar 

  26. 26.

    Zhang YC, Gan FF, Shelar SB, Ng KY, Chew EH (2013) Antioxidant and Nrf2 inducing activities of luteolin, a flavonoid constituent in Ixeris sonchifolia Hance, provide neuroprotective effects against ischemia-induced cellular injury. Food Chem Toxicol 59:272–280. https://doi.org/10.1016/j.fct.2013.05.058

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Esmaeili A, Mousavi Z, Shokrollahi M, Shafaghat A (2013) Antioxidant activity and isolation of Luteoline from Centaurea behen L. Grown in Iran. J Chem 2013:1–5. https://doi.org/10.1155/2013/620305

    CAS  Article  Google Scholar 

  28. 28.

    Boz H (2015) p-Coumaric acid in cereals: presence, antioxidant and antimicrobial effects. Int J Food Sci Technol 50:2323–2328. https://doi.org/10.1111/ijfs.12898

    CAS  Article  Google Scholar 

  29. 29.

    Fang W-S, Sun D-Y, Yang S et al (2019) Discovery of a series of selective and cell permeable beta-secretase (BACE1) inhibitors by fragment linking with the assistance of STD-NMR. Bioorg Chem 92:103253. https://doi.org/10.1016/j.bioorg.2019.103253

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Zheng N, Yuan P, Li C, Wu J, Huang J (2015) Luteolin reduces BACE1 expression through NF-kappaB and through Estrogen Receptor Mediated Pathways in HEK293 and SH-SY5Y cells. J Alzheimers Dis 45:659–671. https://doi.org/10.3233/JAD-142517

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Zhang JS, Zhou SF, Wang Q, Guo JN, Liang HM, Deng JB, He WY (2016) Gastrodin suppresses BACE1 expression under oxidative stress condition via inhibition of the PKR/eIF2alpha pathway in Alzheimer's disease. Neuroscience 325:1–9. https://doi.org/10.1016/j.neuroscience.2016.03.024

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Stoetzer OJ, Pogrebniak A, Scholz M et al (1999) Drug-induced apoptosis in chronic lymphocytic leukemia. Leukemia 13:1873–1880. https://doi.org/10.1038/sj.leu.2401572

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Walton MRMD (2000) Is CREB a key to neuronal survival? Trends Neurosci 23:48–53. https://doi.org/10.1016/S0166-2236(99)01500-3

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Wang Y, Zhang J, Han M et al (2016) SMND-309 promotes neuron survival through the activation of the PI3K/Akt/CREB-signalling pathway. Pharm Biol 54:1982–1990. https://doi.org/10.3109/13880209.2015.1137951

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9:59–71. https://doi.org/10.1111/j.1582-4934.2005.tb00337.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Llorens-Martin M, Jurado J, Hernandez F, Avila J (2014) GSK-3beta, a pivotal kinase in Alzheimer disease. Front Mol Neurosci 7:1–11. https://doi.org/10.3389/fnmol.2014.00046

    CAS  Article  Google Scholar 

  37. 37.

    Teng L, Meng Q, Lu J, Xie J, Wang Z, Liu Y, Wang D (2014) Liquiritin modulates ERK and AKT/GSK3betadependent pathways to protect against glutamateinduced cell damage in differentiated PC12 cells. Mol Med Rep 10:818–824. https://doi.org/10.3892/mmr.2014.2289

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Dal-Cim T, Molz S, Egea J et al (2012) Guanosine protects human neuroblastoma SH-SY5Y cells against mitochondrial oxidative stress by inducing heme oxigenase-1 via PI3K/Akt/GSK-3beta pathway. Neurochem Int 61:397–404. https://doi.org/10.1016/j.neuint.2012.05.021

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Wilson BE, Mochon E, Boxer LM (1996) Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis. Mol Cell Biol 16:5546–5556. https://doi.org/10.1128/MCB.16.10.5546

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Wu X, Liang Y, Jing X et al (2018) Rifampicin prevents SH-SY5Y cells from rotenone-induced apoptosis via the PI3K/Akt/GSK-3beta/CREB signaling pathway. Neurochem Res 43:886–893. https://doi.org/10.1007/s11064-018-2494-y

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Iqbal K-I (2010) Alzheimer's disease, a multifactorial disorder seeking multitherapies. Alzheimers Dement 6:420–424. https://doi.org/10.1016/j.jalz.2010.04.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Wu WY, Dai YC, Li NG et al (2017) Novel multitarget-directed tacrine derivatives as potential candidates for the treatment of Alzheimer's disease. J Enzyme Inhib Med Chem 32:572–587. https://doi.org/10.1080/14756366.2016.1210139

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    McDade E (2019) Why amyloid is still a target for Alzheimer disease clinical trials. J Am Geriatr Soc 67:845–847. https://doi.org/10.1111/jgs.15829

    Article  PubMed  Google Scholar 

  44. 44.

    Willem M, Lammich S, Haass C (2009) Function, regulation and therapeutic properties of β-secretase(BACE1). Semin Cell Dev Biol 20:175–182. https://doi.org/10.1016/j.semcdb.2009.01.003

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Hu X, Das B, Hou H, He W, Yan R (2018) BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. J Exp Med 215:927–940. https://doi.org/10.1084/jem.20171831

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Moussa-Pacha NM, Abdin SM, Omar HA, Alniss H, Al-Tel TH (2019) BACE1 inhibitors: current status and future directions in treating Alzheimer's disease. Med Res Rev. https://doi.org/10.1002/med.21622

    Article  PubMed  Google Scholar 

  47. 47.

    Borghi R, Patriarca S, Traverso N et al (2007) The increased activity of BACE1 correlates with oxidative stress in Alzheimer's disease. Neurobiol Aging 28:1009–1014. https://doi.org/10.1016/j.neurobiolaging.2006.05.004

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Nagai N, Kotani S, Mano Y et al (2017) Ferulic acid suppresses amyloid beta production in the human lens epithelial cell stimulated with hydrogen peroxide. Biomed Res Int 2017:1–9. https://doi.org/10.1155/2017/5343010

    CAS  Article  Google Scholar 

  49. 49.

    Kwak Y-D, Wang R, Li JJ, Zhang Y-W, Xu H, Liao F-F (2011) Differential regulation of BACE1 expression by oxidative and nitrosative signals. Mol Neurodegener 6:1–10. https://doi.org/10.1186/1750-1326-6-17

    CAS  Article  Google Scholar 

  50. 50.

    Tong Y, Zhou W, Fung V, Christensen MA, Qing H, Sun X, Song W (2005) Oxidative stress potentiates BACE1 gene expression and Abeta generation. J Neural Transm (Vienna) 112:455–469. https://doi.org/10.1007/s00702-004-0255-3

    CAS  Article  Google Scholar 

  51. 51.

    Chen ZCZ (2014) Oxidative stress in Alzheimer's disease. Neurosci Bull 30:271–281. https://doi.org/10.1007/s12264-013-1423-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Cobley JN, Fiorello ML, Bailey DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15:490–503. https://doi.org/10.1016/j.redox.2018.01.008

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Pratico D (2008) Oxidative stress hypothesis in Alzheimer's disease: a reappraisal. Trends Pharmacol Sci 29:609–615. https://doi.org/10.1016/j.tips.2008.09.001

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Gill JG, Piskounova E, Morrison SJ (2016) Cancer, oxidative stress, and metastasis. Cold Spring Harb Symp Quant Biol 81:163–175. https://doi.org/10.1101/sqb.2016.81.030791

    Article  PubMed  Google Scholar 

  55. 55.

    Qu L, Chen H, Liu X, Bi L, Xiong J, Mao Z, Li Y (2010) Protective effects of flavonoids against oxidative stress induced by simulated microgravity in SH-SY5Y cells. Neurochem Res 35:1445–1454. https://doi.org/10.1007/s11064-010-0205-4

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Uemura K, Kuzuya A, Shimozono Y, Aoyagi N, Ando K, Shimohama S, Kinoshita A (2007) GSK3beta activity modifies the localization and function of presenilin 1. J Biol Chem 282:15823–15832. https://doi.org/10.1074/jbc.M610708200

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Philip TTL, Yili W, Haiyan Z et al (2013) Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest 123:224–235. https://doi.org/10.1172/JCI64516

    CAS  Article  Google Scholar 

  58. 58.

    Sun H, Wu H, Liu J, Wen J, Zhu Z, Li H (2017) Prenatal stress impairs spatial learning and memory associated with lower mRNA level of the CAMKII and CREB in the adult female rat hippocampus. Neurochem Res 42:1496–1503. https://doi.org/10.1007/s11064-017-2206-z

    CAS  Article  PubMed  Google Scholar 

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This work was financially supported by the National Natural Science Foundation of China (31870786 and 31371331 to J. H., 81273406 to W.-S. F.), and the Drug Innovation Major Project (Grant Nos. 2018ZX09711001-001-001 and 2018ZX09711001-001-003).

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Correspondence to Jian Huang.

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Cheng, C., Zheng, N., Sun, D. et al. A Novel Compound YS-5-23 Exhibits Neuroprotective Effect by Reducing β-Site Amyloid Precursor Protein Cleaving Enzyme 1’s Expression and H2O2-Induced Cytotoxicity in SH-SY5Y Cells. Neurochem Res (2020). https://doi.org/10.1007/s11064-020-03073-4

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  • Alzheimer’s disease
  • BACE1
  • Oxidative stress
  • PI3K/Akt