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Models to study the role of neurotrophic factors in neurodegeneration

  • D. Lindholm
Conference paper

Summary

The physiological functions of neurotrophic factors, such as nerve growth factor (NGF), in supporting the survival and differentiation of specific neurons during early development has in many cases been well established. Recent studies have shown that neurotrophic factors can also protect vulnerable neurons against a variety of mechanical and chemical injuries. The role and the effects of neurotrophic factors in various neurological diseases are however less known. Neurodegenerative diseases such as Parkinson and Alzheimer’s diseases as well as amyotrophic lateral sclerosis (ALS) are characterized by an impaired function and ultimate loss of specific populations of neurons. The study of the ethiology and molecular biology of these diseases has for a long time been hampered by the lack of good animal models mimicked part of the human disease in experimental animals. Here we will discuss some of the current approaches taken in these studies as well as address the important question of the possible beneficial effect of neurotrophic factors in alleviating the symptoms and possibly retarding the course of neurodegenerative diseases.

Keywords

Amyotrophic Lateral Sclerosis Nerve Growth Factor Neurotrophic Factor Cholinergic Neuron Nerve Growth Factor Receptor 
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.

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References

  1. Allen SJ, Dawbarn D, Wilcock GK (1988) Morphometric immunochemical analysis of neurons in the nucleus basalis of Meynert in Alzheimer’s disease. Brain Res 454: 275–281PubMedCrossRefGoogle Scholar
  2. Anderson KJ, Dam D, Lee S, Cotman CW (1988) Basic FGF prevents death of lesioned cholinergic neurons in vivo. Nature 332: 360–361PubMedCrossRefGoogle Scholar
  3. Arakawa Y, Sendtner M, Thoenen H (1990) Survival effect of CNTF on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines. J Neurosci 10: 3507–3515PubMedGoogle Scholar
  4. Barde Y-A (1989) Trophic factors and neuronal survival. Neuron 2: 1525–1534Google Scholar
  5. Berzaghi M da Penha, Cooper J, Castren E, Zafra F, Sofroniew M, Thoenen H, Lindholm D (1993) Cholinergic regulation of BDNF and NGF but not NT-3 mRNA levels in the developing rat hippocampus. J Neurosci 13: 3818–3826Google Scholar
  6. Cooper JD, Lindholm D, Sofroniew MV (1994) Reduced transport of NGF by cholinergic neurons and down-regulated trkA expression in the medial septum of aged rats. Neurosci Lett 62: 625–629Google Scholar
  7. Cote F, Collard J-F, Julien J-P (1993) Progresive neuronopathy in transgenic mice expressing the human neurofilamnet heavy gene: a mouse model for ALS. Cell 73: 35–46PubMedCrossRefGoogle Scholar
  8. Ebendal T (1989) NGF in CNS: experimental data and clinical implications. Prog Growth Factor Res 1: 143–159PubMedCrossRefGoogle Scholar
  9. Ernfors P, Lee K-F, Jaenisch R (1994) Mice lacking BDNF develop with sensory deficits. Nature 368: 147–150PubMedCrossRefGoogle Scholar
  10. Friden P, Walus L, Watson P, Doctrow S, Kozarich J, Bäckman C, Bergman H, Hoffer B, Bloom F, Granholm A (1993) Blood-brain barrier penetration and in vivo activity of an NGF conjugate. Science 259: 373–377PubMedCrossRefGoogle Scholar
  11. Gage F, Kawaja MD, Fischer LJ (1991) Genetically modified cells: application for intracerebral grafting. Trends Neurosci 14: 328–333PubMedCrossRefGoogle Scholar
  12. Glass DJ, Yancopoulos GD (1993) The neurotrophins and their receptors. Trends Cell Biol 3: 262–268PubMedCrossRefGoogle Scholar
  13. Gnahn H, Hefti F, Heumann R, Schwab M, Thoenen H (1983) NGF-mediated increase of choline acetyltransferase (ChAT) in the neornatal rat forebrain: evidence for a physiological role of NGF in the brain. Dev Brain Res 9: 45–52CrossRefGoogle Scholar
  14. Hagg T, Quon D, Higaki J, Varon S (1992) CNTF prevents neuronal degeneration and promotes low affinity NGF receptor expression in the adult rat CNS. Neuron 8:145–158PubMedCrossRefGoogle Scholar
  15. Hefti F (1986) NGF promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 6: 2155–2162PubMedGoogle Scholar
  16. Higgins GA, Koh S, Chen KS, Gage FH (1989) NGF induction of NGF receptor gene expression and cholinergic neuronal hypertrophy within the basal forebrain of the adult rat. Neuron 3: 247–266PubMedCrossRefGoogle Scholar
  17. Hughes RA, Sendtner M, Goldfarb M, Lindholm D, Thoenen H (1993a) Evidence that FGF-5 is a major muscle derived survival factor for cultured spinal motoneurons. Neuron 10: 369–377PubMedCrossRefGoogle Scholar
  18. Hughes RA, Sendtner M, Thoenen H (1993b) Members of several gene families influence survival of rat motoneurons in vitro and in vivo. J Neurosci Res 36: 663–671PubMedCrossRefGoogle Scholar
  19. Klein R, Smeyne RJ, Wurst W, Long LK, Auerbach BA, Joyner AL, Barbacid M (1993) Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 75: 113–122PubMedGoogle Scholar
  20. Koliatsos V, Clatterbuck RE, Winslow JW, Cayouette MH, Price DL (1993) Evidence that BDNF is a trophic factor for motor neurons in vivo. Neuron 10: 359–367PubMedCrossRefGoogle Scholar
  21. Kordower JH, Mufson EJ, Granholm A-C, Hofer B, Friden P (1993) Delivery of trophic factors to the primate brain. Exp Neurol 124: 21–30PubMedCrossRefGoogle Scholar
  22. Leingärtner A, Heisenberg C-P, Kolbeck R, Thoenen H, Lindholm D (1994) BDNF increases NT-3 expression in cerebral granule neurons. J Biol Chem 269: 828–830PubMedGoogle Scholar
  23. Levi-Montalcini R (1987) The nerve growth factor: thirty-five years later. EMBO J 6: 1145–1154PubMedGoogle Scholar
  24. Lewis ME, Neff NT, Contreras PC, Stong DB, Oppenheim RW, Grebow PE, Vaught JL (1993) IGF-1: potential for treatment of motor neuronal disorders. Exp Neurol 124: 73–88PubMedCrossRefGoogle Scholar
  25. Lindholm D, Castren E, Da Penha Berzaghi M, Thoenen H (1993) Effects of neurotransmitters and hormones on neuronal production of neurotrophins. Semin Neurosci 5: 279–283CrossRefGoogle Scholar
  26. Lindholm D, Hartikka J, Da Penha Berzaghi M, Castren E, Tzimagiorgis G, Hughes RA, Thoenen H (1994) FGF-5 promotes differentiation of cultured rat septal cholinergic and raphe serotonergic neurons: comparison with the effects of neurotrophins. Eur J Neurosci 6: 244–252PubMedCrossRefGoogle Scholar
  27. Lärkfors L, Ebendal T, Whittemore S, Hoffer B, Olson L (1987) Decreased level of NGF and its messenger RNA in the aged rat brain. Mol Brain Res 3: 55–60CrossRefGoogle Scholar
  28. Masu Y, Wolf E, Holtmann B, Sendtner M, Brem G, Thoenen H (1993) Disruption of the CNTF gene results in progressive motoneuropathy. Nature 365: 27–32PubMedCrossRefGoogle Scholar
  29. Olson L (1993) NGF and the treatment of Alzheimer s disease. Exp Neurol 124: 5–15PubMedCrossRefGoogle Scholar
  30. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 7: 695–702PubMedCrossRefGoogle Scholar
  31. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donalson D, Goto J, O’Regan JP, Deng H-X, Rahmani Z, Krizus A, McKenna-Yasek D, Cayabyab A, Gaston SM, Berger R, Tanzi RE, Halperin JJ, Herzfeldt B, Van den Berg R, Huang W-Y, Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Periacak-Vance MA, Haines J, Rouleau GA, Gusella JS, Horvitz HR, Brown RH (1993) Mutation in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362: 59–62PubMedCrossRefGoogle Scholar
  32. Schwab M, Otten U, Agid Y, Thoenen H (1979) NGF in the rat CNS: absence of specific retrograde axonal transport and tyrosine hydroxylase induction in locus coeruleus and substantia nigra. Brain Res 168: 473–482PubMedCrossRefGoogle Scholar
  33. Seiler M, Schwab M (1984) Specific retrograde transport of NGF from neocortex to nucleus basalis in the rat. Brain Res 300: 33–39PubMedCrossRefGoogle Scholar
  34. Sendtner M, Kreutzberg GW, Thoenen H (1990) CNTF prevents the degeneration of motor neurons after axotomy. Nature 345: 440–441PubMedCrossRefGoogle Scholar
  35. Sendtner M, Schmalbruch H, Stöckli KA, Carroll P, Kreutzberg GW, Thoenen H (1992a) CNTF prevents degeneration of motor neurons in mouse mutant progressive motor neuropathy. Nature 358: 502–504PubMedCrossRefGoogle Scholar
  36. Sendtner M, Holtmann B, Kolbeck R, Thoenen H, Barde Y-A (1992b) BDNF prevents the death of motoneurons in newborn rats after nerve section. Nature 360: 757–759PubMedCrossRefGoogle Scholar
  37. Snider WD, Johnson EM (1990) Neurotrophic molecules. Ann Neurol 26: 489–506CrossRefGoogle Scholar
  38. Sofroniew MV, Cooper JD (1993) Neurotrophic mechanisms and neuronal degeneration. Semin Neurosci 5: 249–257CrossRefGoogle Scholar
  39. Strada O, Hirsch E, Javoy-Agid F, Lehericy S, Ruberg M, Hauw J, Agid Y (1992) Does loss of NGF receptors precede loss of cholinergic neurons in Alzheimer’s disease? An autoradiography study in the human striatum and basal forebrain. J Neurosci 12: 4766–4776PubMedGoogle Scholar
  40. Thoenen H (1991) The changing scene of neurotrophic factors. Trends Neurosci 14:165–169PubMedCrossRefGoogle Scholar
  41. Thoenen H, Barde Y-A (1980) Physiology of nerve growth factor. Physiol Rev 60:1284–1335PubMedGoogle Scholar
  42. Thoenen H, Hughes R, Sendtner M (1993) Trophic support of motoneurons: physiological, pathophysiological and therapeutic implications. Exp Neurol 124: 47–55PubMedCrossRefGoogle Scholar
  43. Thoenen H, Castren E, Berzaghi M, Blöchl A, Lindholm D (1994) Neurotrophic factors: possibilities and limitations in the treatment of neurodegenerative disorders. Int Acad Biomed Drug Res 7: 197–203Google Scholar
  44. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, DeLong MR (1982) Alzheimer’s disease and senile dementia, loss of neurons in the basal forebrain. Science 215: 1237–1230PubMedCrossRefGoogle Scholar
  45. Yan Q, Elliott J, Snider WD (1992) BDNF rescues spinal motor neurons from axotomy—induced cell death. Nature 360: 753–755PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1997

Authors and Affiliations

  • D. Lindholm
    • 1
  1. 1.Department of Developmental NeuroscienceBMC 587, Uppsala UniversityUppsalaSweden

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