Journal of Molecular Neuroscience

, Volume 20, Issue 3, pp 287–289 | Cite as

The possible role of tissue-type plasminogen activator (tPA) and tPA blockers in the pathogenesis and treatment of Alzheimer’s disease

  • Jerry P. Melchor
  • Robert Pawlak
  • Zulin Chen
  • Sidney Strickland
Alzheimer’s Therapeutics: Anti-Amyloid


Alzheimer’s disease (AD) is the leading cause of cognitive decline in aged individuals. The pathological hallmarks of AD include the formation of neurofibrillary tangles, along with senile plaques that are mainly composed of the amyloid-β (Aβ) peptide. Several lines of evidence implicate the tPA/plasmin system in AD. One type of cell death observed in AD is excitotoxic neuronal damage, and the tPA/plasmin system participates in excitotoxic cell death. Recent in vitro experiments report that the addition of aggregated Aβ peptide to primary cortical neurons leads to the up-regulation of tPA mRNA expression. Additionally, plasmin (activated by tPA) attenuates Aβ neurotoxicity by degrading the peptide and rendering it inactive. However, there is no evidence to demonstrate an in vivo contribution of the tPA/plasmin system in AD. We are currently examining the effects of the tPA/plasmin system on the deposition and toxicity of the Aβ peptide with in vivo paradigms of AD. We hope to define the contribution of the tPA/plasmin system in the development of AD pathology.

Index Entries

tPA plasmin Aβ deposition Aβ degradation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Chen Z.-L. and Strickland S. (1997) Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91, 917–925.PubMedCrossRefGoogle Scholar
  2. Citron M., Oltersdorf T., Haass C., McConlogue L., Hung A. Y., Seubert P., et al. (1992) Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature 360, 672–674.PubMedCrossRefGoogle Scholar
  3. Duff K., Eckman C., Zehr C., Yu X., Prada C. M., Pereztur J., et al. (1996) Increased amyloid-β 42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713.CrossRefGoogle Scholar
  4. Eckman E. A., Reed D. K., and Eckman C. B. (2001) Degradation of the Alzheimer’s amyloid β peptide by endothelin-converting enzyme. J. Biol. Chem. 276, 24,540–24,548.CrossRefGoogle Scholar
  5. Franklin K. B. J. and Paxinos G. (1997) The Mouse Brain in Stereotaxic Coordinates. Academic Press, Inc., San Diego, CA.Google Scholar
  6. Frautschy S. A., Horn D. L., Sigel J. J., Harris-White M. E., Mendoza J. J., Yang F., et al. (1998) Protease inhibitor coinfusion with amyloid beta-protein results in enhanced deposition and toxicity in rat brain. J. Neurosci. 18, 8311–8321.PubMedGoogle Scholar
  7. Haass C., Schlossmacher M. G., Hung A. Y., Vigo-Pelfrey C., Mellon A., Ostaszewski B. L., et al. (1992) Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359, 322–325.PubMedCrossRefGoogle Scholar
  8. Iwata N., Tsubuki S., Takaki Y., Shirotani K., Lu B., Gerard N. P., et al. Metabolic regulation of brain Aβ by neprilysin. Science 292, 1550–1552.Google Scholar
  9. Kingston I. B., Castro M. J., and Anderson S. (1995) In vitro stimulation of tissue-type plasminogen activator by Alzheimer Amyloid beta-peptide analogues. Nat. Med. 1, 138–142.PubMedCrossRefGoogle Scholar
  10. Sappino A.-P., Madani R., Huarte J., Belin D., Kiss J. Z., Wohlwend A., and Vassali J.-D. (1993) Extracellular Proteolysis in the adult murine brain. J. Clin. Invest. 92, 679–685.PubMedGoogle Scholar
  11. Schmued L. C. and Hopkins K. J. (2000) Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res. 874, 123–130.PubMedCrossRefGoogle Scholar
  12. Selkoe D. J. (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 742–760.Google Scholar
  13. Tanzi R. E., Kovacs D. M., Kim T.-W., Moir R. D., Guennette S. Y., and Wasco W. (1996) The gene defects responsible for familial Alzheimer’s disease. Neurobiol. Dis. 3, 159–168.CrossRefGoogle Scholar
  14. Tsirka S. E., Gualandris A., Amaral D. G., and Strickland S. (1995) Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 377, 340–344.PubMedCrossRefGoogle Scholar
  15. Tsirka S. E., Rogove A. D., and Strickland S. (1996) Neuronal cell death and tPA. Nature 384, 123–124.CrossRefGoogle Scholar
  16. Tsirka S. E., Rogove A. D., Bugge T. H., Degen J. L., and Strickland S. (1997) An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J. Neurosci. 17, 543–552.PubMedGoogle Scholar
  17. Tucker H. M., Kihiko M., Caldwell J. N., Wright S., Kawarabayashi T., Price D., et al. (2000a) The plasmin system is induced by and degrades amyloid-beta aggregates. J. Neurosci. 20, 3937–3946.PubMedGoogle Scholar
  18. Tucker H. M., Kihiko-Ehmann M., Wright S., Rydel R. E., and Estus S. (2000b) Tissue plasminogen activator requires plasminogen to modulate amyloid-beta neurotoxicity and deposition. J. Neurochem. 75, 2172–2177.PubMedCrossRefGoogle Scholar
  19. Vassalli J.-D., Sappino A.-P., and Belin D. (1991) The plasminogen activator/plasmin system. J. Clin. Invest. 88, 1067–1072.PubMedCrossRefGoogle Scholar
  20. Vekrellis K., Ye Z., Qiu W. Q., Walsh D., Hartley D., Chesneau V., et al. (2000) Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J. Neurosci. 20, 1657–1665.PubMedGoogle Scholar
  21. Wyss-Coray T., Masliah E., Mallory M., McConlogue L., Johnson-Wood K., Lin C., and Mucke L. (1997) Amyloidogenic role of the cytokine TGF-β1 in transgenic mice and Alzheimer’s disease. Nature 389, 603–606.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Jerry P. Melchor
    • 1
  • Robert Pawlak
    • 1
  • Zulin Chen
    • 1
  • Sidney Strickland
    • 1
  1. 1.The Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew York

Personalised recommendations