Role of Trophic Factors in Neuronal Aging

  • J. Regino Perez-Polo
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 265)


Neuronal cell death is an event associated with the pathophysiology of nerve injury, stroke and aging that is also a positive regulatory element in neuronal development. Whereas in all the aforementioned, the neurite outgrowth, as a part of the spectrum of responses by the surviving neurons, has been extensively studied at the molecular level; less is known about the molecular mechanisms that determine cell survival, except for the many classical biological experiments that have established that in vertebrate development, neuronal cell death is, in large measure but not uniquely, under the control of neuronotrophic factors such as the nerve growth factor protein, NGF (Thoenen et al., 1981). Two hypotheses have been proposed to explain the phenomena resulting in neuronal death. One hypothesis is that neurons are particularly susceptible to free radical damage because of their very low basal endogenous levels of antioxidants and antioxidant enzymes and that neuronotrophic factors acting through their respective cell surface receptors can shift the oxidant-antioxidant balance through induction of antioxidant enzymes (Perez-Polo et al., 1986). The second hypothesis proposes that there are “suicide genes” whose repression by NGF results in cell survival (Martin et al., 1988). Following axotomy to peripheral sympathetic and sensory neurons or the more central projections of the basal forebrain into the hippocampal areas, NGF has also been shown to be necessary to peripheral regeneration and to sparing effects on cholinergic basal forebrain neurons following deafferentation. NGF has dramatic trophic effects on cholinergic neurons of the CNS in vitro, a regeneration paradigm (Bostwick et al, 1987; Hatanaka et al, 1988). In aged rodent and human CNS and PNS, there are reported decreases in the levels of NGF and its receptor, NGFR (Goedert et al, 1986; Angelucci et al, 1988; Uchida and Tonionaga, 1987). In the periphery, NGF has well documented effects on certain neuronal and non-neuronal cells alike whose physiological relevance is not understood in a definitive fashion (Levi-Montalcini, 1987; Lillien and Claude, 1985; Thorpe, et al., 1988).


PC12 Cell Neurite Outgrowth Neuronal Cell Death Cholinergic Neuron Basal Forebrain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agranoff, B.W., 1984, Lipid peroxidation and membrane aging. Neurobiol. of Aging, 5: 337–338.CrossRefGoogle Scholar
  2. Angelucci, L., Ramacci, M.T., Taglialatela G., Hulsebosch, C., Morgan, B., Werrbach-Perez, K and Perez-Polo, R., 1988, Nerve growth factor binding in aged rat central nervous system: effect of acetyl-L-carnitine, JNR 20: 491–496.Google Scholar
  3. Angelucci, L., Ramacci, M.T., Amenta, F., Lorentz, G. and Maccari, F., 1988, Acetyl-L-carnitine in the rat’s hippocampus aging: morphological, endocrine and behavioral correlates. In: Neural Development & Regeneration, Cellular & Molecular Aspects, A. Gorio, J.R. Perez-Polo, J. deVellis, B. Haber, eds., Springer-Verlag, Heidelberg, pp. 57–66.CrossRefGoogle Scholar
  4. Bostwick, J.R., Appel, S.H., Perez-Polo, J.R., 1987, Distinct influences of NGF and a CNS cholinergic factor on medial septal explants. Brain Res. 422: 92 - 98.CrossRefGoogle Scholar
  5. Buck, C.R., Martinez, H.J., Black, I.B., Chao, M.V., 1987, Developmental regulated expression of the NGF Receptor gene in the PNS and brain. Proc. Natl. Acad. Sci. 84: 3060–3063.Google Scholar
  6. Chao, M.V., Bothwell, M.A., Ross, A.H., Koprowski, H., Lanahan, A.A., Buck, C.R., Sehgal, A., 1986, Gene transfer and mol. cloning of the human NGFR. Science 232: 518–521.CrossRefGoogle Scholar
  7. Cutler, R.G., 1985, Peroxide-producing potential of tissues: inverse correlation with longevity of mammalian species. Proc. Natl. Acad. Sci. USA, 82: 4798–4802.Google Scholar
  8. Davies, K.J.A., Protein damage and degradation by oxygen radicals. J. Biol. Chem. 262: 9895–9920.Google Scholar
  9. Demopoulos, H.B., Flamm, E.S., Pietronigro, D.D., Seligman, M.L., 1980, The free radical pathology & the microcirculation in the major CNS disorders. Acta Physiol Scand. 492: (suppl): 43–57.Google Scholar
  10. Goedert, M., Fine, A., Hunt, S.P., Ullrich, A., 1986, NGF mRNA in PNS & CNS tissues & in the human CNS: lesion effects in the rat brain and levels in Alzheimer’s Disease. Mol. Brain Res. 1:85-92. Greene, L.A., Shooter, E.M., 1980, The Nerve Growth Factor: Biochemistry, synthesis, and mechanism of action. Annu Rev. Neurosci. 3: 353–402.Google Scholar
  11. Grob, P.M., Ross, A.H., Koprowski, H., Bothwell, M., 1985, Characterization of the human melanoma NGFR. J. Biol. Chem. 260: 8044–8049.Google Scholar
  12. Hatanaka, H., Nihonmatsu, I and Tsukui, H., 1988, Nerve growth factor promotes survival of cultured magnocellular cholinergic neurons from nucleus basalis of meynert in postnatal rats. Neurosci. Lett. 90: 63–68.Google Scholar
  13. Hosang, M., Shooter, E.M. 1987, The internalization of NGF by high affinity receptors on pheochromocytoma PC12 cells. EMBO J. 6: 1197–1202.Google Scholar
  14. Khan, T., Green, B., Perez-Polo, J.R., 1987, Effect of Injury on NGF uptake by sensory ganglia. J. Neurosci. Res. 18: 562–567.Google Scholar
  15. Levi-Montalcini, R, 1987, The NGF 35 Years Later, Science 237: 1154–1162.CrossRefGoogle Scholar
  16. Lillien, L.E., Claude, P., 1985, NGF is a mitogen for cultured chromaffin cells. Nature 317: 632–634.CrossRefGoogle Scholar
  17. Lyons, C.R., Stach, R.W., Perez-Polo, J.R., 1983, Binding constants of isolated NGFR from different species. Biochem. Biophys. Res. Comm. 115: 368–374.Google Scholar
  18. Marchetti, D., Perez-Polo, J.R., 1987, NGFR in human neuroblastoma cells. J. Neurochem. 49: 475–486.CrossRefGoogle Scholar
  19. Marchetti, D., Stach, R.W., Saneto, R.P., deVellis, J., Perez-Polo, J.R., 1987, Binding constants of soluble NGFR in rat oligodendrocytes & astrocytes in culture. Biochem. Biophys. Res. Comm. 147: 422–427.Google Scholar
  20. Perez-Polo, J.R., Reynolds, C.P., Tiffany-Castiglioni, E., Ziegler, M., Schulze, I., Werrbach-Perez, K., 1982, NGF effects on human neuroblastoma lines: A model system. In: Proteins in the Nervous System: Structure and Functions. B. Haber, J.R. Perez-Polo, J.D. Coulter eds., Alan R. Liss, NY;285–299.Google Scholar
  21. Perez-Polo, J.R., 1985, Neuronotrophic Factors. In: Cell Cultures in the Neurosciences, J.R. Bottenstein, G. Sato eds., Plenum Press, New York, 3: 95–123.Google Scholar
  22. Perez-Polo, J.R., Werrbach-Perez, K.,1985, Effects of NGF on the in vitro response of neurons to injury. In: Recent Achievements in Restorative Neurol Neuron Functions and Dysfunctions J. Eccles, J.R. Dimitrijevic, eds., Karger 30: 321–377.Google Scholar
  23. Perez-Polo, J.R., Apffel, L., Werrbach-Perez, K., 1986, Role of CNS and PNS trophic factors on free radical mediated aging events. Clin. Neuropharm. 9: 98–100.Google Scholar
  24. Perez-Polo, R., Werrbach-Perez, K., 1987, In vitro model of neuronal aging and develop. in the nervous system. In: Model Systems of Develop, and Aging of the Nerv. System. A. Vernadakis, ed., Martinus Nijhoff, Boston, pp. 433–442.Google Scholar
  25. Perez-Polo, J.R., 1987, Neuronal Factors. CRC, Boca Raton: 1–202.Google Scholar
  26. Perez-Polo, J.R., Werrbach-Perez, K., 1988, Role of NGF in neuronal injury & survival. In: Neural Develop. & Regeneration, Cellular & Molecular Aspects, A. Gorio, J.R. Perez-Polo, J. de Veins, B Haber, eds., Springer Verlag, Heidelberg, 399–410.Google Scholar
  27. Radeke, M.J., Misko, T.P., Hasu, C., Herzenberg, L.A., Shooter, E.M., 1987, Gene transfer and molecular cloning of rat NGFR. Nature 325: 593–597.CrossRefGoogle Scholar
  28. Stach, R.W., Perez-Polo, J.R., 1987, Binding of NGF to its receptor. J. Neurosci. Res. 17: 1–10.Google Scholar
  29. Thoenen, H., Barde, Y.A., Davies, A.M., Johnson, J.E., 1981, Neuronotrophic factors & neuronal death. Ciba Found. Symp. 126: 838–840.Google Scholar
  30. Thorpe, L.W., Morgan, B., Beck, C., Werrbach-Perez, K., Perez-Polo, JR., 1988, NGF and the immune system. In: Neural Development & Regeneration Cellular & Molecular Aspects” A. Gorio, J.R. Perez-Polo, J. deVellis, B. Haber, eds., Springer Verlag, Heidelberg pp. 583–594.Google Scholar
  31. Uchida, Y, Tonionaga, M, 1987, Loss of NGFR in sympathetic ganglia form aged mice. Biochem. Biophys. Res. Comm. 146: 797801.Google Scholar
  32. Whittemore, S.R., Seiger, A., 1987, The Expression, localization and functional significance of beta-NGF in the Central Nervous System, Brain Res. Rev., 12:439-464. Whittemore, S.R., Person, H., Ebendal, T., Larkfors, L., Larhammar, D., Ericsson, A., 1988, Structure and Expression of beta-NGF in the rat Central Nervous System. In: Neural Development & Regeneration Cellular & Molecular Aspects, A. Gorio, J.R. Perez-Polo, J. deVellis, B. Haber eds., Springer-Verlag, Heidelberg, pp. 245–256.Google Scholar
  33. Wright, L.L., Beck, C., Perez-Polo, J.R. 1987, Sex differences in NGF levels in SCG and pineals. Int. J. Dev. Neurosci., 5: 383–390.Google Scholar
  34. Wright, L.L., Marchetti, D., Perez-Polo, J.R., 1988, Effects of gonadal steroids on NGF receptors in sympathetic and sensory ganglia of neonatal rats. Int. J. Dev. Neurosci., 6: 3, 217–222.CrossRefGoogle Scholar
  35. Yankner, B.S., Shooter, E.M. 1982, The biology and mechanism of action of NGF. Annu Rev. Biochem. 51: 845–868.Google Scholar
  36. Yau, Q., Johnson, Jr., E.M., 1987, A quantitative study of the developmental expression of the NGF receptor in rats. Dev. Biol. 121: 139–148.Google Scholar
  37. Yip, H.K.,Johnson, R.M. 1984, Developing DRG neurons required trophic support form their central processes: Evidence for a role of retrogradely transported NGF from the CNS system to the PNS. Proc. Natl. Acad. Sci. 81:6245–6249.Google Scholar
  38. Zimmermann, A, Sutter, A., 1983, NGFR on glial cells in sensory neurons. EMBO J. 2: 879–885.Google Scholar

Copyright information

© Springer Science+Business Media New York 1990

Authors and Affiliations

  • J. Regino Perez-Polo
    • 1
  1. 1.Dept. of HBC & GUniv. of Texas Medical Br.GalvestonUSA

Personalised recommendations