Advertisement

Neurochemical Research

, Volume 36, Issue 5, pp 801–811 | Cite as

RETRACTED ARTICLE: Fuzhisan, a Chinese Herbal Medicine, Inhibits Beta-Amyloid-Induced Neurotoxicity and Tau Phosphorylation Through Calpain/Cdk5 Pathway in Cultured Cortical Neurons

  • Zhaoxu Zhang
  • Ruiping Zhao
  • Ying Tang
  • Shirong Wen
  • Desheng Wang
  • Jiping Qi
Original Paper

Abstract

It has been shown that β-amyloid (Aβ) induced hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer’s disease (AD), and deregulation of cyclin-dependent kinase 5 (Cdk5) activity is involved in the abnormal tau phosphorylation. The cleavage of neuron-specific Cdk5 activator, p35, to p25, mediated by calpain and calcium, deregulates Cdk5 activity and promotes neurodegeneration. Fuzhisan (FZS), a Chinese herbal complex prescription that has been used for the treatment of AD for over 15 years, is known to enhance the cognitive ability in AD patients. In this study, we investigated the neuroprotective effects and potential molecular mechanisms of FZS against Aβ25–35-induced toxicity in cultured cortical neurons. We revealed that FZS attenuated Aβ25–35-induced neurotoxicity in a dose-dependent manner. FZS inhibited Aβ25–35-induced activation of Cdk5 and decreased tau hyperphosphorylation although it did not directly inhibit Cdk5. In addition, FZS also blocked Aβ25–35-induced calcium influx, calpain activation and decreased cleavage of p35 to p25.

Keywords

Fuzhisan (FZS) Alzheimer’s disease Tau Cyclin-dependent kinase 5 (CDK5) p35 p25 

Abbreviations

AD

Alzheimer’s disease

β-amyloid

NFTs

neurofibrillary tangles

GSK3β

Glycogen synthase kinase 3 beta

Cdk5

Cyclin-dependent kinase 5

FZS

Fuzhisan

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 30973106) and Natural Science Foundation of HeiLongJiang Province (No.CB08C309).

References

  1. 1.
    Selkoe DJ (1994) Alzheimer’s disease: a central role for amyloid. J Neuropathol Exp Neurol 53:438–447PubMedCrossRefGoogle Scholar
  2. 2.
    Kondo J, Honda T, Mori H et al (1988) The carboxyl third of tau is tightly bound to paired helical filaments. Neuron 1:827–834PubMedCrossRefGoogle Scholar
  3. 3.
    Lee VM, Balin BJ, Otvos L Jr et al (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251:675–678PubMedCrossRefGoogle Scholar
  4. 4.
    Busciglio J, Lorenzo A, Yeh J et al (1995) Beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14:879–888PubMedCrossRefGoogle Scholar
  5. 5.
    Masliah E, Sisk A, Mallory M et al (2001) Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. J Neuropathol Exp Neurol 60:357–368PubMedGoogle Scholar
  6. 6.
    Chen X, Huang T, Zhang J et al (2008) Involvement of calpain and p25 of CDK5 pathway in ginsenoside Rb1’s attenuation of beta-amyloid peptide25–35-induced tau hyperphosphorylation in cortical neurons. Brain Res 1200:99–106PubMedCrossRefGoogle Scholar
  7. 7.
    Le WD, Xie WJ, Kong R et al (1997) Beta-amyloid-induced neurotoxicity of a hybrid septal cell line associated with increased tau phosphorylation and expression of beta-amyloid precursor protein. J Neurochem 69:978–985PubMedCrossRefGoogle Scholar
  8. 8.
    Zhou J, Wang H, Feng Y et al (2010) Increased expression of cdk5/p25 in N2a cells leads to hyperphosphorylation and impaired axonal transport of neurofilament proteins. Life Sci 86:532–537PubMedCrossRefGoogle Scholar
  9. 9.
    Rapoport M, Dawson HN, Binder LI et al (2002) Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci USA 99:6364–6369PubMedCrossRefGoogle Scholar
  10. 10.
    Leschik J, Welzel A, Weissmann C et al (2007) Inverse and distinct modulation of tau-dependent neurodegeneration by presenilin 1 and amyloid-beta in cultured cortical neurons: evidence that tau phosphorylation is the limiting factor in amyloid-beta-induced cell death. J Neurochem 101:1303–1315PubMedCrossRefGoogle Scholar
  11. 11.
    Mandelkow EM, Biernat J, Drewes G et al (1993) Microtubule-associated protein tau, paired helical filaments, and phosphorylation. Ann N Y Acad Sci 695:209–216PubMedCrossRefGoogle Scholar
  12. 12.
    Patrick GN, Zukerberg L, Nikolic M et al (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622PubMedCrossRefGoogle Scholar
  13. 13.
    Alvarez A, Munoz JP, Maccioni RB (2001) A Cdk5–p35 stable complex is involved in the beta-amyloid-induced deregulation of Cdk5 activity in hippocampal neurons. Exp Cell Res 264:266–274PubMedCrossRefGoogle Scholar
  14. 14.
    Koh SH, Noh MY, Kim SH (2008) Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3. Brain Res 1188:254–262PubMedCrossRefGoogle Scholar
  15. 15.
    Alvarez A, Toro R, Caceres A et al (1999) Inhibition of tau phosphorylating protein kinase cdk5 prevents beta-amyloid-induced neuronal death. FEBS Lett 459:421–426PubMedCrossRefGoogle Scholar
  16. 16.
    Lopes JP, Oliveira CR, Agostinho P (2010) Neurodegeneration in an Abeta-induced model of Alzheimer’s disease: the role of Cdk5. Aging Cell 9:64–77PubMedCrossRefGoogle Scholar
  17. 17.
    Dhavan R, Tsai LH (2001) A decade of CDK5. Nat Rev Mol Cell Biol 2:749–759PubMedCrossRefGoogle Scholar
  18. 18.
    Cheung ZH, Ip NY (2004) Cdk5: mediator of neuronal death and survival. Neurosci Lett 361:47–51PubMedCrossRefGoogle Scholar
  19. 19.
    Cruz JC, Tsai LH (2004) A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr Opin Neurobiol 14:390–394PubMedCrossRefGoogle Scholar
  20. 20.
    Dhariwala FA, Rajadhyaksha MS (2008) An unusual member of the Cdk family: Cdk5. Cell Mol Neurobiol 28:351–369PubMedCrossRefGoogle Scholar
  21. 21.
    Lee MS, Kwon YT, Li M et al (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405:360–364PubMedCrossRefGoogle Scholar
  22. 22.
    Noble W, Olm V, Takata K et al (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38:555–565PubMedCrossRefGoogle Scholar
  23. 23.
    Utreras E, Maccioni R, Gonzalez-Billault C (2009) Cyclin-dependent kinase 5 activator p35 over-expression and amyloid beta synergism increase apoptosis in cultured neuronal cells. Neuroscience 161:978–987PubMedCrossRefGoogle Scholar
  24. 24.
    Lee KY, Clark AW, Rosales JL et al (1999) Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain. Neurosci Res 34:21–29PubMedCrossRefGoogle Scholar
  25. 25.
    Cruz JC, Tseng HC, Goldman JA et al (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40:471–483PubMedCrossRefGoogle Scholar
  26. 26.
    Kerokoski P, Suuronen T, Salminen A et al (2002) Cleavage of the cyclin-dependent kinase 5 activator p35 to p25 does not induce tau hyperphosphorylation. Biochem Biophys Res Commun 298:693–698PubMedCrossRefGoogle Scholar
  27. 27.
    Hsiao YH, Chen PS, Yeh SH et al (2008) N-acetylcysteine prevents beta-amyloid toxicity by a stimulatory effect on p35/cyclin-dependent kinase 5 activity in cultured cortical neurons. J Neurosci Res 86:2685–2695PubMedCrossRefGoogle Scholar
  28. 28.
    Zheng YL, Kesavapany S, Gravell M et al (2005) A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons. EMBO J 24:209–220PubMedCrossRefGoogle Scholar
  29. 29.
    Crespo-Biel N, Camins A, Pallas M et al (2009) Evidence of calpain/cdk5 pathway inhibition by lithium in 3-nitropropionic acid toxicity in vivo and in vitro. Neuropharmacology 56:422–428PubMedCrossRefGoogle Scholar
  30. 30.
    Li XL, Wang de S, Zhao BQ et al (2008) Effects of Chinese herbal medicine fuzhisan on aged rats. Exp Gerontol 43:853–858PubMedCrossRefGoogle Scholar
  31. 31.
    Zhao J, Wang D, Duan S et al (2009) Analysis of fuzhisan and quantitation of baicalin and ginsenoside Rb(1) by HPLC-DAD-ELSD. Arch Pharm Res 32:989–996PubMedCrossRefGoogle Scholar
  32. 32.
    Gang BZ SWD, Wang CL (2005) The efficacy of Fuzhisan in patients with Alzheimer’s disease. Chin J Apoplexy Nerv Dis 22:527–529Google Scholar
  33. 33.
    Wen SR, Wang DS, Zhang JY (2005) Effect of Fuzhisan on the area of neurosome and the length of axon. Chin J Clin Rehabil 9:241–243Google Scholar
  34. 34.
    Sul D, Kim HS, Lee D et al (2009) Protective effect of caffeic acid against beta-amyloid-induced neurotoxicity by the inhibition of calcium influx and tau phosphorylation. Life Sci 84:257–262PubMedCrossRefGoogle Scholar
  35. 35.
    Li G, Faibushevich A, Turunen BJ et al (2003) Stabilization of the cyclin-dependent kinase 5 activator, p35, by paclitaxel decreases beta-amyloid toxicity in cortical neurons. J Neurochem 84:347–362PubMedCrossRefGoogle Scholar
  36. 36.
    Maas T, Eidenmuller J, Brandt R (2000) Interaction of tau with the neural membrane cortex is regulated by phosphorylation at sites that are modified in paired helical filaments. J Biol Chem 275:15733–15740PubMedCrossRefGoogle Scholar
  37. 37.
    Bojarski L, Herms J, Kuznicki J (2008) Calcium dysregulation in Alzheimer’s disease. Neurochem Int 52:621–633PubMedCrossRefGoogle Scholar
  38. 38.
    Cho JH, Johnson GV (2004) Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau’s ability to bind and stabilize microtubules. J Neurochem 88:349–358PubMedCrossRefGoogle Scholar
  39. 39.
    Augustinack JC, Schneider A, Mandelkow EM et al (2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 103:26–35PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Neurologythe First Affiliated Hospital, Harbin Medical UniversityHarbinChina
  2. 2.Department of PathologyThe First Affiliated Hospital, Harbin Medical UniversityHarbinChina

Personalised recommendations