Skip to main content

Advertisement

SpringerLink
Log in

PMS777, a New Cholinesterase Inhibitor with Anti-Platelet Activated Factor Activity, Regulates Amyloid Precursor Protein Processing In Vitro

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized clinically by progressive impairment of memory and cognition. Previous data have shown that beta-amyloid (Aβ) cascade plays a central role in AD pathophysiology and thus drugs regulate amyloid precursor protein (APP) metabolism may have therapeutic potential. Here the effects of PMS777, a new cholinesterase inhibitor with anti-platelet activated factor activity, on APP processing were investigated. Using SH-SY5YAPP695 cells, it showed that PMS777 treatment caused significant decreased secretion of sAPPα into the conditioned media without affecting cellular holoAPP synthesis. When PC12 cells were incubated with PMS777, the same effect was observed. The data also indicated that 10 μM PMS777 incubation decreased the release of Aβ42 into the cell media as compared with vehicle group in SH-SY5YAPP695 cells. Pretreatment of cells with M-receptor scopolamine antagonized the decreased secretion of sAPPα induced by PMS777, but N-receptor α-bungarotoxin pretreatment did not have such an effect. These results indicated that PMS777 could modulate APP processing in vitro and that decreasing Aβ generation might demonstrate its therapeutic potential in AD.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766

    PubMed  CAS  Google Scholar 

  2. Stein TD, Anders NJ, DeCarli C, Chan SL, Mattson MP, Johnson JA (2004) Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPsw mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothesis. J Neurosci 24:7707–7717

    Article  PubMed  CAS  Google Scholar 

  3. Awasthi A, Matsunaga Y, Yamada T (2005) Amyloid-beta causes apoptosis of neuronal cells via caspase cascade, which can be prevented by amyloid-beta-derived short peptides. Exp Neurol 196:282–289

    Article  PubMed  CAS  Google Scholar 

  4. Jang JH, Surh YJ (2005) Beta-amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-activated protein kinase-NF-kappa B signaling pathway. Free Radic Biol Med 38:1604–1613

    Article  PubMed  CAS  Google Scholar 

  5. Grossberg GT (2005) Rationalizing therapeutic approaches in Alzheimer’s disease. CNS Spectr 10:17–21

    PubMed  Google Scholar 

  6. Nitsch RM, Slack BE, Wurtman TJ, Growdon JH (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258:304–307

    Article  PubMed  CAS  Google Scholar 

  7. Shaw KT, Utsuki T, Rogers J, Yu Q, Sambamurti K, Brossi A, Ge Y, Lahiri DK, Greig NH (2001) Phenserine regulates translation of β-amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development. Proc Natl Acad Sci USA 98:7605–7610

    Article  PubMed  CAS  Google Scholar 

  8. Racchi M, Sironi M, Caprera A, König G, Govoni S (2001) Short- and long-term effect of acetylcholinesterase inhibition on the expression and metabolism of the amyloid precursor protein. Mol Psychiatry 6:520–528

    Article  PubMed  CAS  Google Scholar 

  9. Zhang H, Yan H, Tang X (2004) Huperzine A enhances the level of secretory amyloid precursor protein and protein kinase C-α in intracerebroventricular β-amyloid-(1–40) infused rats and human embryonic kidney 293 Swedish mutant cells. Neurosci Lett 360:21–24

    Article  PubMed  CAS  Google Scholar 

  10. Zimmermann M, Gardoni F, Marcello E, Colciaghi F, Borroni B, Padovani A, Cattabeni F, Di Luca M (2004) Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines. J Neurochem 90:1489–1499

    Article  PubMed  CAS  Google Scholar 

  11. Le Texier L, Favre E, Redeuilh C, Blavet N, Bellahsene T, Dive G, Pirotzky E, Godfroid JJ (1996) Structure-activity relationships in platelet-activating factor (PAF). 7. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors. Synthesis and PAF-antagonistic activity. J Lipid Mediat Cell Signal 13:189–205

    Article  PubMed  CAS  Google Scholar 

  12. Le Texier L, Favre E, Ronzani N, Massicot F, Blavet N, Pirotzky E, Godfroid JJ (1996) Structure-activity relationships in platelet-activating factor (PAF). 8. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors: anti-acetylcholinesterase activity and comparative SAR. J Lipid Mediat Cell Signal 13:207–222

    Article  PubMed  CAS  Google Scholar 

  13. Ezoulin MJ, Li J, Wu G, Dong CZ, Ombetta JE, Chen HZ, Massicot F, Heymans F (2005) Differential effect of PMS777, a new type of acetylcholinesterase inhibitor, and galanthamine on oxidative injury induced in human neuroblastoma SK-N-SH cells. Neurosci Lett 389:61–65

    Article  PubMed  CAS  Google Scholar 

  14. Li J, Huang H, Miezan Ezoulin JM, Gao XL, Massicot F, Dong CZ, Heymans F, Chen HZ (2007) Pharmacological profile of PMS777, a new AChE inhibitor with PAF antagonististic activity. Int J Neuropsychopharmacol 10:21–29

    Article  PubMed  CAS  Google Scholar 

  15. Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman S, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L (2001) BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet 10:1317–1324

    Article  PubMed  CAS  Google Scholar 

  16. Tsai JY, Wolfe MS, Xia W (2002) The search for gamma-secretase and development of inhibitors. Curr Med Chem 9:1087–1096

    PubMed  CAS  Google Scholar 

  17. Vassar R (2002) Beta-secretase (BACE) as a drug target for Alzheimer’s disease. Adv Drug Deliv Rev 54:1589–1602

    Article  PubMed  CAS  Google Scholar 

  18. Bigl V, Roßner S (2003) Amyloid precursor protein processing in vivo-insights from a chemically-induced constitutive overactivation of protein kinase C in guinea pig brain. Curr Med Chem 10:871–882

    Article  PubMed  CAS  Google Scholar 

  19. Ercheberrigaray R, Tan M, Dewachter I, Kuiperi C, Vander AI, Wera S, Qiao L, Bank B, Nelson TJ, Kozikowski AP, van Leuven F, Alkon DL (2004) Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proc Natl Acad Sci USA 101:11141–11146

    Article  Google Scholar 

  20. Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer’s disease mouse model. J Clin Invest 113:1456–1464

    PubMed  CAS  Google Scholar 

  21. Lahiri DK, Farlow MR, Sambamurti K (1998) The secretion of amyloid β-peptides is inhibited in the tacrine-treated human neuroblastoma cells. Mol Brain Res 62:131–140

    Article  PubMed  CAS  Google Scholar 

  22. Lahiri DK, Farlow MR, Sambamurti K, Nall C (1997) The effect of tacrine and leupeptin on the secretion of the beta-amyloid precursor protein in Hela cells. Life Sci 61:1985–1992

    Article  PubMed  CAS  Google Scholar 

  23. Mazzucchelli M, Porrello E, Villetti G, Pietra C, Govoni S, Racchi M (2003) Characterization of the effect of ganstigmine (CHF2819) on amyloid precursor protein metabolism in SH-SY5Y neuroblastoma cells. J Neural Transm 110:935–947

    Article  PubMed  CAS  Google Scholar 

  24. Pakaski M, Rakonczay Z, Kasa P (2001) Reversible and irreversible acetylcholinesterase inhibitors cause changes in neuronal amyloid precursor protein processing and protein kinase C level in vitro. Neurochem Int 38:219–226

    Article  PubMed  CAS  Google Scholar 

  25. Yogev-Falach M, Amit T, Bar-Am O, Weinstock M, Youdim MB (2002) The involvement of mitogen-activated protein (MAP) kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline. FASEB J 16:1674–1676

    PubMed  CAS  Google Scholar 

  26. Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM (2005) Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging 26:645–654

    Article  PubMed  CAS  Google Scholar 

  27. Eckman EA, Reed DK, Eckman CB (2001) Degradation of the Alzheimer’s amyloid beta peptide by endothelin-converting enzyme. J Biol Chem 276:24540–24548

    Article  PubMed  CAS  Google Scholar 

  28. Hemming ML, Selkoe DJ (2005) Amyloid β-protein is degraded by cellular angiotensin converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem 280:37644–37650

    Article  PubMed  CAS  Google Scholar 

  29. Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M, Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC (2000) Identification of the major Abeta1–42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 6:143–150

    Article  PubMed  CAS  Google Scholar 

  30. Melchor JP, Pawlak R, Strickland S (2003) The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta degradation and inhibits Abeta-induced neurodegeneration. J Neurosci 23:8867–8871

    PubMed  CAS  Google Scholar 

  31. 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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from State Key Basic Research Program (2006CB500706), Shanghai Key Project of Basic Science Research (07DJ14005) and Program for Outstanding Medical Academic Leader (LJ 06003).

Author information

Author notes

  1. Hong-Qi Yang

    Present address: Department of Neurology, Henan Provincal People’s Hospital, Zhengzhou, 450003, Henan Province, People’s Republic of China

Authors and Affiliations

  1. Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China

    Hong-Qi Yang, Zhi-Kun Sun, Yan-Xin Zhao, Jing Pan, Mao-Wen Ba, Guo-Qiang Lu, Jian-Qing Ding & Sheng-Di Chen

  2. Institute of Health Science, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China

    Hong-Qi Yang, Zhi-Kun Sun, Jing Pan, Guo-Qiang Lu, Jian-Qing Ding & Sheng-Di Chen

  3. Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China

    Hong-Zhuan Chen

Authors
  1. Hong-Qi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi-Kun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan-Xin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mao-Wen Ba
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guo-Qiang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian-Qing Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hong-Zhuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sheng-Di Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hong-Zhuan Chen or Sheng-Di Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, HQ., Sun, ZK., Zhao, YX. et al. PMS777, a New Cholinesterase Inhibitor with Anti-Platelet Activated Factor Activity, Regulates Amyloid Precursor Protein Processing In Vitro. Neurochem Res 34, 528–535 (2009). https://doi.org/10.1007/s11064-008-9816-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-008-9816-4

Keywords

Search

Navigation