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Breviscapine exerts neuroprotective effects through multiple mechanisms in APP/PS1 transgenic mice

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Abstract

Alzheimer's disease (AD) is one of the most serious neurodegenerative diseases and is characterized by progressive cognitive impairment and multiple neurological changes. To date, there are no effective drugs to delay or cure AD. Breviscapine (Bre) is an active ingredient of flavonoids extracted from breviscapus. Previous research suggests that Bre is an effective medicine for the prevention and treatment of AD. In the present study, we sought to explore the molecular mechanisms responsible for short-term beneficial effects of Breviscapine on Aβ burden, neuronal and synaptic, cognitive function in APP/PS1 transgenic mice at 6 months age. Our results showed that 3 months of intraperitoneal treatment with Bre rescued learning deficits, relieved memory retention, improved the ability to explore the outside world, markedly decreased Aβ burden, attenuated function of neocortical and hippocampal neuron, and increased the synaptic proteins levels in the brain of APP/PS1 mice by decreasing BACE1, promoting Aβ-degrading enzyme IDE expression, suppressing RAGE expression, and regulating p38/p53/NT4 pathway. This finding provides more evidence of neuroprotective effects and action mechanisms of Bre antagonist AD, suggesting that Bre may have potential as anti-AD agent.

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References

  1. The L (2016) Alzheimer's disease: expedition into the unknown. Lancet 4:388–2713. https://doi.org/10.1016/S0140-6736(16)32457-6

    Article  Google Scholar 

  2. Jiang T, Chang RC, Rosenmann H, Yu JT (2015) Advances in alzheimer's disease: from bench to bedside. Biomed Res Int 11:202–676. https://doi.org/10.1155/2015/202676

    Article  Google Scholar 

  3. Uddin MS, Kabir MT, Al Mamun A, Abdel-Daim MM, Barreto GE, Ashraf GM (2019) Apoe and alzheimer's disease: evidence mounts that targeting apoe4 may combat alzheimer's pathogenesis. Mol Neurobiol 56:2450–2465. https://doi.org/10.1007/s12035-018-1237-z

    Article  CAS  PubMed  Google Scholar 

  4. Gustavsson A, Green C, Jones RW, Förstl H, Simsek D, de Reydet de Vulpillieres F, Luthman S, Adlard N, Bhattacharyya S, Wimo A (2017) Current issues and future research priorities for health economic modelling across the full continuum of alzheimer's disease. Alzheimers Dement 13:312–321. https://doi.org/10.1016/j.jalz.2016.12.005

    Article  PubMed  Google Scholar 

  5. Chinese Pharmacopoeia Commission (2010) Pharmacopoeia of the People's Republic of China. China Medical Science and Technology Press part 1:138

  6. Zhang WD, Chen WS, Kong DY (2000) Study on chemical composition of herba Erigeron breviscapus (I). J Second Mil Med Univ 2:143–145. https://doi.org/10.16781/j.0258-879x.2000.02.022

    Article  CAS  Google Scholar 

  7. Yan YZ (2008) Research progress on the protective mechanism of breviscapine on cerebral ischemia reperfusion injury. Sichuan J Physiol Sci 30:129–130.

    Google Scholar 

  8. Shi YH, Miao H, Su PF (2008) Effect of breviscapine on memory impairment induced by d-galactose in mice. Lishizhen Med Mater Med Res 19:1445–1446. https://doi.org/10.3969/j.issn.1008-0805.2008.06.077

    Article  CAS  Google Scholar 

  9. Mao JQ, Qiu Y, Li TJ (2017) Effects of breviscapine on learning and memory function in rats with traumatic brain injury. Chin J Pharm 23(167–169):240. https://doi.org/10.3969/j.issn.1008-9926.2007.03.003

    Article  Google Scholar 

  10. Zeng YQ, Cui YB, Gu JH, Liang C, Zhou XF (2018) Scutellarin mitigates abeta-induced neurotoxicity and improves behavior impairments in ad mice. Molecules 9:23. https://doi.org/10.3390/molecules23040869

    Article  CAS  Google Scholar 

  11. Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 17:157–165. https://doi.org/10.1016/s1389-0344(01)00067-3

    Article  CAS  PubMed  Google Scholar 

  12. Malm T, Koistinaho J, Kanninen K (2011) Utilization of APPswe/PS1dE9 transgenic mice in research of alzheimer's disease: focus on gene therapy and cell-based therapy applications. Int J Alzheimers Dis 2011:517160. https://doi.org/10.4061/2011/517160

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zeng YQ, Wang YJ, Zhou XF (2014) Effects of (-) epicatechin on the pathology of app/ps1 transgenic mice. Front Neurol 5:69. https://doi.org/10.3389/fneur.2014.00069

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M (2010) Alzheimer's disease: clinical trials and drug development. Lancet Neurol 9:702–716. https://doi.org/10.1016/S1474-4422(10)70119-8

    Article  CAS  PubMed  Google Scholar 

  15. Schonrock N, Matamales M, Ittner LM, Götz J (2012) Microrna networks surrounding app and amyloid-beta metabolism–implications for alzheimer's disease. Exp Neurol 235:447–454. https://doi.org/10.1016/j.expneurol.2011.11.013

    Article  CAS  PubMed  Google Scholar 

  16. Haass C, Selkoe DJ (2017) Soluble protein oligomers in neurodegeneration: lessons from the alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112. https://doi.org/10.1038/nrm2101

    Article  CAS  Google Scholar 

  17. Kobayashi D, Zeller M, Cole T, Buttini M, McConlogue L, Sinha S, Freedman S, Morris RG, Chen KS (2008) Bace1 gene deletion: impact on behavioral function in a model of alzheimer's disease. Neurobiol Aging 29:861–873. https://doi.org/10.1016/j.neurobiolaging.2007.01.002

    Article  CAS  PubMed  Google Scholar 

  18. Probst G, Xu YZ (2012) Small-molecule bace1 inhibitors: a patent literature review (2006–2011). Expert Opin Ther Pat 22:511–540. https://doi.org/10.1517/13543776.2012.681302

    Article  CAS  PubMed  Google Scholar 

  19. Yu SL, Wong CK, Szeto CC, Li EK, Cai Z, Tam LS (2015) Members of the receptor for advanced glycation end products axis as potential therapeutic targets in patients with lupus nephritis. Lupus 24:675–686. https://doi.org/10.1177/0961203314559631

    Article  CAS  PubMed  Google Scholar 

  20. Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP (2005) Understanding rage, the receptor for advanced glycation end products. J Mol Med (Berl) 83:876–886. https://doi.org/10.1007/s00109-005-0688-7

    Article  CAS  Google Scholar 

  21. Wan W, Cao L, Liu L, Zhang C, Kalionis B, Tai X, Li Y, Xia S (2015) Abeta(1–42) oligomer-induced leakage in an in vitro blood-brain barrier model is associated with up-regulation of rage and metalloproteinases, and down-regulation of tight junction scaffold proteins. J Neurochem 134:382–393. https://doi.org/10.1111/jnc.13122

    Article  CAS  PubMed  Google Scholar 

  22. Deane R, Du YS, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B (2003) Rage mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9:907–913. https://doi.org/10.1038/nm890

    Article  CAS  PubMed  Google Scholar 

  23. Gilbert BJ (2013) The role of amyloid beta in the pathogenesis of alzheimer's disease. J Clin Pathol 66:362–366. https://doi.org/10.1136/jclinpath-2013-201515

    Article  CAS  PubMed  Google Scholar 

  24. Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, Frosch MP, Selkoe DJ (2003) Enhanced proteolysis of beta-amyloid in app transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40:1087–1093. https://doi.org/10.1016/s0896-6273(03)00787-6

    Article  CAS  PubMed  Google Scholar 

  25. 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 USA 100:4162–4167. https://doi.org/10.1073/pnas.0230450100

    Article  CAS  PubMed  Google Scholar 

  26. Carew TJ (1996) Molecular enhancement of memory formation. Neuron 16:5–8. https://doi.org/10.1016/s0896-6273(00)80016-1

    Article  CAS  PubMed  Google Scholar 

  27. Reustle A, Torzewski M (2018) Role of p38 mapk in atherosclerosis and aortic valve sclerosis. Int J Mol Sci. https://doi.org/10.3390/ijms19123761

    Article  PubMed  PubMed Central  Google Scholar 

  28. Roy S, Rana A, Akhter Y, Hande MP, Banerjee B (2018) The role of p38 mapk pathway in p53 compromised state and telomere mediated DNA damage response. Mutat Res Genet Toxicol Environ Mutagen 836:89–97. https://doi.org/10.1016/j.mrgentox.2018.05.018

    Article  CAS  PubMed  Google Scholar 

  29. Mattson MP (2004) Pathways towards and away from alzheimer's disease. Nature 430:631–639. https://doi.org/10.1038/nature02621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. LaFerla FM, Hall CK, Ngo L, Jay G (1996) Extracellular deposition of beta-amyloid upon p53-dependent neuronal cell death in transgenic mice. J Clin Invest 98:1626–1632. https://doi.org/10.1172/JCI118957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lapresa R, Agulla J, Sanchez-Moran I, Zamarreño R, Prieto E, Bolaños JP, Almeida A (2019) Amyloid-ss promotes neurotoxicity by cdk5-induced p53 stabilization. Neuropharmacology 146:19–27. https://doi.org/10.1016/j.neuropharm.2018.11.019

    Article  CAS  PubMed  Google Scholar 

  32. Hou Y, Aboukhatwa MA, Lei DL, Manaye K, Khan I, Luo Y (2010) Anti-depressant natural flavonols modulate bdnf and beta amyloid in neurons and hippocampus of double tgad mice. Neuropharmacology 58:911–920. https://doi.org/10.1016/j.neuropharm.2009.11.002

    Article  CAS  PubMed  Google Scholar 

  33. Cotman CW (2005) The role of neurotrophins in brain aging: a perspective in honor of regino perez-polo. Neurochem Res 30:877–881. https://doi.org/10.1007/s11064-005-6960-y

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Yunnan Biopharmaceutical Major Project (2018ZF002), Union Foundation of Yunnan Applied Research Project 2017FE468(-183), and Innovation Team Project of Yunnan Education Department.

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Authors and Affiliations

  1. Institute of Neuroscience, College of Basic Medicine, Kunming Medical University, Kunming, 650500, China

    Zhu Li & Jin-Tao Li

  2. Yunnan Key Laboratory of Stem Cells and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, 650500, China

    Xiao-Bei Zhang, Juan-Hua Gu & Yue-Qin Zeng

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  1. Zhu Li
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Li, Z., Zhang, XB., Gu, JH. et al. Breviscapine exerts neuroprotective effects through multiple mechanisms in APP/PS1 transgenic mice. Mol Cell Biochem 468, 1–11 (2020). https://doi.org/10.1007/s11010-020-03698-7

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