Skip to main content

Advertisement

SpringerLink
Log in

Wogonin increases β-amyloid clearance and inhibits tau phosphorylation via inhibition of mammalian target of rapamycin: potential drug to treat Alzheimer’s disease

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Many molecular lesions have been detected in AD, of which the most commonly observed is the accumulation of misfolded proteins, including β-amyloid (Aβ40 and Aβ42) and tau, in the aging brain. The mammalian target of rapamycin (mTOR) pathway mediates Aβ clearance through autophagy and regulates tau phosphorylation via glycogen synthase kinase-3β (GSK3β). Thus, mTOR becomes an important therapeutic target for AD. However, no mTOR inhibitor has yet been marketed to treat AD. Here, we discovered a natural product, wogonin, which could potently promote Aβ clearance in the primary neural astrocytes and significantly decrease Aβ secretion in SH-SY5Y-APP and BACE1 cells [SH-SY5Y cells stably expressing the human amyloid precursor protein (APP) and β-secretase (BACE1)] through the mTOR/autophagy signaling pathway. Additionally, further research revealed that wogonin inhibited the activity of GSK3β via mTOR inhibition, finally leading to tau phosphorylation reduction in SH-SHY5Y cells and primary neural astrocytes. In conclusion, our study identified a small molecule, wogonin, which could effectively promote Aβ clearance and decrease tau phosphorylation, and highlighted its therapeutic potential for AD treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Grundke-Iqbal I, Iqbal K, Tung YC et al (1986) Abnormal phosphorylation of the microtubule associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Kirschner DA, Abraham C, Selkoe DJ (1986) X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation. Proc Natl Acad Sci USA 83(2):503–507 (PMID: 3455785)

  3. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  PubMed  Google Scholar 

  4. Younkin SG (1998) The role of A beta 42 in Alzheimer’s disease [J]. J Physiol Paris 92(3–4):289–292

    Article  CAS  PubMed  Google Scholar 

  5. Vingtdeux V, Chandakkar P, Zhao H et al (2011) Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. FASEB J 25:219–231 (PMID: 20852062)

  6. Zhu Z, Yan J, Jiang W et al (2013) Arctigenin effectively ameliorates memory impairment in Alzheimer’s disease model mice targeting both beta-amyloid production and clearance. J Neurosci 33:13138–13149

    Article  CAS  PubMed  Google Scholar 

  7. Tang Z, Bereczki E, Zhang H, Wang S, Li C, Ji X, Branca RM, Lehtiö J, Guan Z, Filipcik P, Xu S, Winblad B, Pei JJ (2013) Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease. J Biol Chem 288:15556–15570

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Caccamo A, Magri A, Medina DX et al (2013) mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell 12:370–380

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Yue GG, Chan BC, Kwok HF et al (2012) Screening for anti-inflammatory and bronchorelaxant activities of 12 commonly used Chinese herbal medicines. Phytother Res 26:915–925

    Article  PubMed  Google Scholar 

  10. Li BQ, Fu T, Yan YD et al (1993) Inhibition of HIV infection by baicalin–a flavonoid compound purified from Chinese herbal medicine. Cell Mol Biol Res 39:119–124

    CAS  PubMed  Google Scholar 

  11. Bubeck Wardenburg J, Patel RJ, Schneewind O (2007) Surface proteins and exotoxins are required for the pathogenesis of Staphylococcus aureus pneumonia. Infect Immun 75:1040–1044 (PMID: 17101657)

  12. Zhao K, Song X, Huang Y, Yao J, Zhou M, Li Z, You Q, Guo Q, Lu N (2014) Wogonin inhibits LPS-induced tumor angiogenesis via suppressing PI3K/Akt/NF-κB signaling. Eur J Pharmacol 737:57–69

    Article  CAS  PubMed  Google Scholar 

  13. Chen XM, Bai Y, Zhong YJ, Xie XL, Long HW, Yang YY, Wu SG, Jia Q, Wang XH (2013) Wogonin has multiple anti-cancer effects by regulating c-Myc/SKP2/Fbw7α and HDAC1/HDAC2 pathways and inducing apoptosis in human lung adenocarcinoma cell line A549. PLoS One 8(11):e79201

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Lin B (2011) Polyphenols and neuroprotection against ischemia and neurodegeneration. Mini Rev Med Chem 11(14):1222–1238

    CAS  PubMed  Google Scholar 

  15. Landreth GE, Cramer PE, Lakner MM et al (2013) Response to comments on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340:924-g (PMID: 23704556)

  16. Klionsky DJ, Abdalla FC (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8(4):445–544

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Song HR, Cheng JJ, Miao H et al (2009) Scutellaria flavonoid supplementation reverses ageing-related cognitive impairment and neuronal changes in aged rats. Brain Inj 23:146–153

    Article  PubMed  Google Scholar 

  19. Jeong K, Shin YC, Park S et al (2011) Ethanol extract of Scutellaria baicalensis Georgi prevents oxidative damage and neuroinflammation and memorial impairments in artificial senescense mice. J Biomed Sci 18:14

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Shang YZ, Gong MY, Zhou XX et al (2001) Improving effects of SSF on memory deficits and pathological changes of neural and immunological systems in senescent mice. Acta Pharmacol Sin 22:1078–1083

    CAS  PubMed  Google Scholar 

  21. Kim DH, Kim S, Jeon SJ et al (2008) The effects of acute and repeated oroxylin A treatments on Abeta(25–35)-induced memory impairment in mice. Neuropharmacology 55:639–647

    Article  CAS  PubMed  Google Scholar 

  22. Hwang YK, Jinhua M, Choi BR et al (2011) Effects of Scutellaria baicalensis on chronic cerebral hypoperfusion-induced memory impairments and chronic lipopolysaccharide infusion-induced memory impairments. J Ethnopharmacol 137:681–689

    Article  PubMed  Google Scholar 

  23. Guertin DA, Sabatini DM (2005) An expanding role for mTOR in cancer. Trends Mol Med 11:353–361 (Pubmed:16002336)

  24. Li X, Alafuzoff I, Soininen H et al (2005) Levels of mTOR and its downstream targets 4EBP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain. FEBS J 272:4211–4220

    Article  CAS  PubMed  Google Scholar 

  25. Abel T, Lattal KM (2001) Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr Opin Neurobiol 11:180–187

    Article  CAS  PubMed  Google Scholar 

  26. Caccamo A, Majumder S, Richardson A et al (2010) Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 285:13107–13120

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Spilman P, Podlutskaya N, Hart MJ et al (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid beta levels in a mouse model of Alzheimer’s disease. PLoS One 5:e9979

    Article  PubMed Central  PubMed  Google Scholar 

  28. Yu C, Wang L, Lv B et al (2008) TMEM74, a lysosome and autophagosome protein, regulates autophagy. Biochem Biophys Res Commun 369:622–629

    Article  CAS  PubMed  Google Scholar 

  29. Tang Z, Bereczki E, Zhang H et al (2013) Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease. J Biol Chem 288:15556–15570

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Talbi A, Zhao D, Liu Q, Li J, Fan A, Yang W, Han X, Chen X (2014) Pharmacokinetics, tissue distribution, excretion and plasma protein binding studies of wogonin in rats. Molecules 19(5):5538–5549

    Article  PubMed  Google Scholar 

  31. Bloom GS (2014) Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71(4):505–508

    Article  PubMed  Google Scholar 

  32. Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A (2002) Tau is essential to β-amyloid-induced neurotoxicity. Proc Natl Acad Sci USA 99(9):6364–6369 (PMID:11959919)

  33. King ME, Kan HM, Baas PW, Erisir A, Glabe CG, Bloom GS (2006) Tau-dependent microtubule disassembly initiated by prefibrillar β-amyloid. J Cell Biol 175(4):541–546 (PMID:17101697)

Download references

Conflict of interest

The authors report no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Neurology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, 230001, China

    Yuyou Zhu

  2. Department of Dermatology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, 230001, China

    Juan Wang

Authors
  1. Yuyou Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuyou Zhu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, Y., Wang, J. Wogonin increases β-amyloid clearance and inhibits tau phosphorylation via inhibition of mammalian target of rapamycin: potential drug to treat Alzheimer’s disease. Neurol Sci 36, 1181–1188 (2015). https://doi.org/10.1007/s10072-015-2070-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-015-2070-z

Keywords

Search

Navigation