NGF and Alzheimer’s disease: a model for trophic factor therapy in neurodegeneration

  • B. Knüsel
  • F. Hefti
Conference paper
Part of the Key Topics in Brain Research book series (KEYTOPICS)


A review on recent research progress in neurotrophic factors and their implication for experimental therapy of Alzheimer’s disease is given. The status of NGF mechanisms in AD is not fully understood, although NGF administration in animal studies is suggested to counter at cholinergic atrophy present in AD. Limited clinical trials have been performed with NGF in AD, and effective therapy in AD will require protection of vulnerable neuronal populations. The possibilities of NGF treatment of CNS diseases including AD are intracerebral infusion, slow-releasing implants, implantation of cells producing recombinant NGF or local injection of genetic material producing active fragments or small molecules that pass the blood-brain barrier. NGF administration is expected to improve functional performance of surviving cells, but larger clinical trials are needed to confirm preliminary encouraging results of neurotrophic factor therapy.


Nerve Growth Factor Neurotrophic Factor Cholinergic Neuron Basal Forebrain Basal Forebrain Cholinergic Neuron 
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. Aebischer P, Winn SR, Tresco PA, Jaeger CB, Greene LA (1991) Transplantation of polymer encapsulated neurotransmitter secreting cells: effect of the encapsulation technique. J Biomech Eng 113:178–183.PubMedCrossRefGoogle Scholar
  2. Alderson RF, Alterman AL, Barde YA, Lindsay RM (1990) Brain derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture. Neuron 5:297–306.PubMedCrossRefGoogle Scholar
  3. Baird A, Schubert D, Ling N, Guillemin R (1988) Receptor-and heparin-binding domains of basic fibroblast growth factor. Proc Natl Acad Sci USA 85:2324–2328.PubMedCrossRefGoogle Scholar
  4. Borg J, et al (1987) Neurotrophic effect of naturally occurring long-chain fatty alcohols on cultured CNS neurons. FEB 213:406–410.CrossRefGoogle Scholar
  5. Carswell S, Hoffmann EK, Clopton-Hartpence K, Wilcox HM, Lewis ME (1992) Induction of NGF by isoproterenol, 4-methylcatechol and serum occurs by three distinct mechanisms. Mol Brain Res 15:145–150.PubMedCrossRefGoogle Scholar
  6. Clatterbuck RE, Price DL, Koliatsos VE (1993) Ciliary neurotrophic factor prevents retrograde neuronal death the adult central nervous system. Proc Natl Acad Sci 90:2222–2226.PubMedCrossRefGoogle Scholar
  7. Cummings BJ, Yee GJ, Cotman CW (1992) bFGF promotes the survival of entorhinal layer II neurons after perforant path axotomy. Brain Res 591:271–276.PubMedCrossRefGoogle Scholar
  8. D’Mello SR, Heinrich G (1991) Structural and functional identification of regulatory regions and cis elements surrounding the nerve growth factor gene promoter. Mol Brain Res 11:255–264.PubMedCrossRefGoogle Scholar
  9. Daitz HM, Powell TPS (1954) Studies on the connections of the fornix system. J Neurol Neurosurg Psychiatry 17:75–82.PubMedCrossRefGoogle Scholar
  10. Davies P, Maloney AJF (1976) Lancet II:1403.CrossRefGoogle Scholar
  11. DeKosky ST, Harbaugh RE, Schmitt FA, Bakay RAE, Chui HC, Knopman DS, Reeder TM, Shetter AG, Senter HJ, Markesbery WR and the Intraventricular Bethanechol Study Group (1992) Cortical biopsy in Alzheimer’s disease: diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations. Ann Neurol 32:625–632.PubMedCrossRefGoogle Scholar
  12. Eppstein DA, Marsh YV, Schryver BB, Bertics PJ (1989) Inhibition of epidermal growth factor/transforming growth factor-alpha-stimulated cell growth by a synthetic peptide. J Cell Physiol 141:420–430.PubMedCrossRefGoogle Scholar
  13. Etienne P, Robitaille Y, Wood P, Gauthier S, Nair NP, Quirion R (1986) Nucleus basalis neuronal loss, neuritic plaques and choline acetyltransferase activity in advanced Alzheimer’s disease. Neuroscience 19:1279–91.PubMedCrossRefGoogle Scholar
  14. Francis PT, Palmer AM, Sioms NR, Bowen DM, Davison AN, Esiri MM, Neary D (1985) Neurochemical studies of early-onset Alzheimer’s disease. Possible influence on treatment. Lancet 4:7–11.Google Scholar
  15. Friden PM, Walus LR, Watson P, Doctrow SR, Kozarich JW, Backman C, Bergman H, Hoffer B, Blomm F, Granholm AC (1993) Blood-brain barrier penetration and in vivo activity of an NGF conjugate. Science 259:373–376.PubMedCrossRefGoogle Scholar
  16. Friedman WJ, Ibanez CF, Hallbook F, Persson H, Cain LD, Dreyfus CF, Black LB (1993) Differential actions of neurotrophins in the locus coeruleus and basal forebrain. Exp Neurol 119:72–78.PubMedCrossRefGoogle Scholar
  17. Fukuyama Y, Otoshi Y, Nakamura K, Kodama M, Nagasawa M, Hasegawa T, Okazaki H, Sugawara M (1992) Neurotrophic sesquiterpene-neoligans from Magnolia obovata: structure and neurotrophic activity. Tetrahedron 48:377–392.CrossRefGoogle Scholar
  18. Gage FH, Wictorin K, Fischer W, Williams LR, Varon S, Bjorklund A (1986) Life and death of cholinergic neurons: in the septal and diagnoal band region following complete fimbria formix transections. Neuroscience 19:241–256.PubMedCrossRefGoogle Scholar
  19. Gether U, Johanson TE, Snider RM, Lowe JA, Nakanishi S, Schwartz TW (1993) Different binding epitopes on the NK1 receptor for substance P and non-peptide antagonist. Nature 362:345–348.PubMedCrossRefGoogle Scholar
  20. Gibbs RB, Pfaff DW (1992) Effects of estrogen and fimbria/fornix transection on p75NGFR and ChAT expression in the medial septum and diagonal band of Broca. Exp Neurol 116:23–39.PubMedCrossRefGoogle Scholar
  21. Goedert M, Fine A, Dawbarn D, Wilcock GK, Chao MV (1989) Nerve growth factor receptor mRNA distribution in human brain: normal levels in basal forebrain in Alzheimer’s disease. Mol Brain Res 5:1–7.PubMedCrossRefGoogle Scholar
  22. Hagg T, Fass-Holmes B, Vahlsing HL, Manthorpe M, Conner JM, Varon S (1989) Nerve growth factor (NGF) reverses axotomy-induced decreases in choline acetyltransferase, NGF receptor and size of medial septum cholinergic neurons. Brain Res 505:29–38.PubMedCrossRefGoogle Scholar
  23. Hagg T, Manthorpe M, Vahlsing HL, Varon S (1988) Delayed treatment with nerve growth factor reverses the apparent loss of cholinergic neurons after acute brain damage. Exp Neurol 101:303–312.PubMedCrossRefGoogle Scholar
  24. Harbaugh RE, Reeder TM, Senter HJ, Knopman DS, Baskin DS, et al (1989) Intracerebroventricular bethanechol chloride infusion in Alzheimer’s disease: results of a collaborative double-blind study. J Neurosurg 71:481–486.PubMedCrossRefGoogle Scholar
  25. Hartikka J, Hefti F (1988) Comparison of nerve growth factor’s effects on development of septum, striatum, and nucleus basalis cholinergic neurons in vitro. J Neurosci Res 21:352–364.PubMedCrossRefGoogle Scholar
  26. Hefti F (1986) Nerve growth factor (NGF) promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 6:2155–2162.PubMedGoogle Scholar
  27. Hefti F (1993) Neurotrophic factor therapy for nervous system degenerative diseases. Neuron (in press).Google Scholar
  28. Hefti F, Schneider LS (1989) Rationale for the planned clinical trials with nerve growth factor in Alzheimer’s disease. Psych Dev 4:297–315.Google Scholar
  29. Hefti F, David A, Hartikka J (1984) Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase activity in adult rats with partial septo-hippocampal lesions. Brain Res 293:305–311.PubMedCrossRefGoogle Scholar
  30. Hefti F, Hartikka J, Eckenstein F, Gnahn H, Heumann R, Schwab M (1985) Nerve growth factor (NGF) increases cholinergic acetyltransferase but not survival or fiber outgrowth of cultured fetal septal cholinergic neurons. Neuroscience 14:55–68.PubMedCrossRefGoogle Scholar
  31. Hefti F, Hartikka J, Knüsel B (1989) Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neuro-degenerative diseases. Neurobiol Aging 10:515–533.PubMedCrossRefGoogle Scholar
  32. Hoffman D, Wahlberg L, Aebischer P (1990) NGF released from a polymer matrix prevents loss of ChAT expression in basal forebrain neurons following a Fimbria-Fornix lesion. Exp Neurol 110:39–44.PubMedCrossRefGoogle Scholar
  33. Honegger P, Lenoir D (1982) Nerve growth factor (NGF) stimulation of cholinergic telencephalic neurons in aggregating cell cultures. Dev Brain Res 3:229–239.CrossRefGoogle Scholar
  34. Ibanez CF, Hallbook F, Ebendal T, Persson H (1990) Structure-function studies of nerve growth factor: functional importance of highly conserved amino acid residues. EMBO J 9:1477–1483.PubMedGoogle Scholar
  35. Ip NV, McClain J, Barrezueta NX, Aldrich TH, Pan L, Li Y, Wiegand SJ, Friedman B, Davis S, Yancopoulos G (1993a) The alpha component of the CNTF receptor is required for signaling and defines potential CNTF targets in the adult and during development. Neuron 10:89–102.PubMedCrossRefGoogle Scholar
  36. Isaacson LG, Saffran BN, Crutcher KA (1990) Intracerebral NGF infusion induces hyperinnervation of cerebral blood vessels. Neurobiol Aging 11:51–55.PubMedCrossRefGoogle Scholar
  37. Kaplan DR, Perkins A, Morrison DK (1992) Signal transduction by receptor tyrosine kinases. In: McGuire WL (ed) Oncogenes and tumor suppressor genes in human malignancies. Kluwer Academic Publishers, Norwell MA.Google Scholar
  38. Katoh-Semba R, Semba R, Kashiwamata S, Kato K (1991) Elevated concentrations of beta-nerve growth factor in selected tissues from senescence-accelerated mice (SAM-P/8). Mech Ageing Dev 59:163–175.PubMedCrossRefGoogle Scholar
  39. Kawagishi H, Ando M, Sakamoto H, Yoshida S, Ojima F, Ishiguro Y, Ukai N, Furokawa S (1991) Hericenones cerebrolysin, D and E, stimulators of nerve growth factor (NGF)-synthesis, from the mushroom Hericium erinaceum. Tetrahedron Lett 32:4561–4564.CrossRefGoogle Scholar
  40. Knüsel B, Hefti F (1992) K-252 compounds: modulators of neurotrophin signal tranduction. J Neurochem 59:1987–1996.PubMedCrossRefGoogle Scholar
  41. Knüsel B, Winslow JW, Rosenthal A, Burton LE, Seid DP, Nikolics K, Hefti F (1991) Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin-3. Proc Natl Acad Sci USA 88:961–965.PubMedCrossRefGoogle Scholar
  42. Knüsel B, Beck Kd, Winslow JW, Rosenthal A, Burton LE, Widmer HR, Nikolics K, Hefti F (1992a) Brain derived neurotrophic factor administration protects basal forebrain cholinergica but not nigral dopaminergic neurons from degenerative changes after axotomy in the adult rat brain. J Neurosci 12: 4391–4402.PubMedGoogle Scholar
  43. Knüsel B, Kaplan DR, Winslow JW, Rosenthal A, Burton LE, Beck KD, Rabin S, Nikolics K, Hefti F (1992b) K-252b selectively potentiates cellular actions and trk tyrosine phosphorylation mediated by neurotrophin-3. J Neurochem 59:715–722.PubMedCrossRefGoogle Scholar
  44. Knüsel B, Rabin S, Hefti F, Kaplan DR (1994) Regulated neurotrophin receptor responsiveness during neuronal migration and early differentiation. J Neurosci 14:1542–1554.PubMedGoogle Scholar
  45. Koliatsos VE, Clatterbuck RE, Nauta HJW, Knüsel B, Burton LE, Hefti F, Mobley WC, Price DL (1991) Human nerve growth factor prevents degeneration of basal forebrain cholinergic neurons in primates. Ann Neurol 30:831–840.PubMedCrossRefGoogle Scholar
  46. Koliatsos VE, Clatterbuck RE, Winslow JW, Cayouette MH, Price DL (1993) Evidence that brain-derived neurotrophic factor is a trohic factor for motor neurons in vivo. Neuron 10:359–367.PubMedCrossRefGoogle Scholar
  47. Konishi Y, Kotts CE, Bullock LD, Tou JS, Johnson DA (1989) Fragments of bovine insulin-like growth factors I and II stimulate proliferation of rat L6 myoblast cells. Biochemistry 28:8872–8877.PubMedCrossRefGoogle Scholar
  48. Kosik KS (1992) Alzheimer’s disease: a cell biological perspective. Science 256:780–783.PubMedCrossRefGoogle Scholar
  49. Lapchak PA, Araujo DM, Carswell S, Hefti F (1993a) Distribution of (125I) nerve growth factor in the rat brain following an intraventricular injection: sequestration by trkA mRNA expressing septal neurons. Neuroscience 52:575–585.PubMedCrossRefGoogle Scholar
  50. Lapchak PA, Araujo DM, Hefti F (1993b) Cholinergic regulation of hippocampal brain-derived neurotrophic factor mRNA expression: evidence from lesion and chronic cholinergic drug treatment studies. Neuroscience 53:379–394.PubMedCrossRefGoogle Scholar
  51. Lehericy S, Hirsch EC, Cervera-Pierot P, Hersh LB, Bakchine S, Piette F, Duyckaerts Cerebrolysin Hauw JJ, Javoy-Agid F, Agid Y (1993) Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer’s disease J Comp Neurol 330:15–31.PubMedCrossRefGoogle Scholar
  52. Levi-Montalcini R (1987) The nerve growth factor: thirty-five years later. EMBO J 6:1145–1154.PubMedGoogle Scholar
  53. Lindholm D, Hengerer B, Heumann R, Carroll P, Thoenen H (1990) Glucocorticoid hormones negatively regulate nerve growth factor expression in vivo and in cultured rat fibroblasts. Eur J Neurosci 2:795–801.PubMedCrossRefGoogle Scholar
  54. Maysinger D, Jalsenjak I, Cuello AC (1992) Microencapsulated nerve growth factor: effects on the forebrain neurons following devascularizing cortical lesions. Neurosci Lett 140:71–74.PubMedCrossRefGoogle Scholar
  55. Mobley WC, Neve RL, Prusiner SB, McKinley MP (1988) Nerve growth factor induces gene expression for prion-and Alzheimer’s beta-amyloid proteins. Proc Natl Acad Sci USA 85:9811–9815.PubMedCrossRefGoogle Scholar
  56. Nakagawara A, Arima-Nakagawara M, Scavarda NJ, Azar CG, Cantor AB, Brodeur GM (1993) Association between high levels of expression of the trk gene and favorable outcome in human neuroblastoma. N Engl J Med 328:847–854.PubMedCrossRefGoogle Scholar
  57. O’Brien TS, Svendsen CN, Isacson O, Sofroniew MV (1990) Loss of true blue labelling from the medial septum following transection of the fimbria-fornix: evidence for the death of cholinergic and non-cholinergic neurons. Brain Res 508:249–256.PubMedCrossRefGoogle Scholar
  58. Ohyagi Y, Tabira T (1993) Effect of growth factors and cytokines on expression of amyloid beta protein precursor mRNAs in cultured neural cells. Mol Brain Res 18:127–132.PubMedCrossRefGoogle Scholar
  59. Olson L, Nordberg A, von Holst H, Backman L, Ebendahl T, Alafuzoff I, Amberla K, Hartvig P, Herlitz A, Lilja A, Lundquist H, Langstron B, Meyerson B, Persson A, Viitanen M, Winblad B, Seiger A (1992) Nerve growth factor affects 11C-nicotine binding, blood flow, EEG and verbal episodic memory in an Alzheimer patient. J Neural Transm [P-D Sect] 4:79–95.CrossRefGoogle Scholar
  60. Olton DS (1990) Dementia animal models of the cognitive impairments following damage to the basal forebrain cholinergic system. Brain Res Bull 25:499–502.PubMedCrossRefGoogle Scholar
  61. Olton D, Markowska A, Voytko ML, Givens B, Gorman L, Wenk G (1991) Basal forebrain cholinergic system: a functional analysis. Adv Exp Med Biol 295:353–72.PubMedGoogle Scholar
  62. Pardridge WM (1991) Transnasal and intraventricular delivery of drugs. In: Pardridge WM (ed) Peptide drug delivery to the brain. Raven Press, New York, pp 99–122.Google Scholar
  63. Park TH, Mytilineou C (1992) Protection from l-methyl-4-phenylpyridinium (MPP+) toxicity and stimulation of regrowth of MPP +-damaged dopaminergic fibers by treatment of mesencephalic cultures with EGF and basic FGF. Brain Res 599:83–97.PubMedCrossRefGoogle Scholar
  64. Paul JW, DaVanzo JP (1992) 1,1,3 Tricyano-2-amino-l propene (Triap) stimulates choline acetyltransferase activity in vitro and in vivo. Dev Brain Res 67:113–120.CrossRefGoogle Scholar
  65. Phillips HS, Hains JM, Laramee GR, Rosenthal A, Winslow JW (1990) Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons. Science 250:290–292.PubMedCrossRefGoogle Scholar
  66. 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 7:695–702.PubMedCrossRefGoogle Scholar
  67. Price DL (1986) New perspectives on Alzheimer’s disease. Ann Rev Neurosci 9:489–512.PubMedCrossRefGoogle Scholar
  68. Rosenberg MB, Friedmann T, Robertson RC, Tuszynksi M, Wolff JA, Breakfield XO, Gage FH (1988) Grafting genetically modified cells to the damaged brain: restorative effects of NGF expression. Science 242:1575–1578.PubMedCrossRefGoogle Scholar
  69. Shintami A, Ohno Y, Kaisho Y, Sasada R, Igarashi K (1993) Identification of the functional regulatory region of the neurotrophin-3 gene promotor. Mol Brain Res 17:129–134.CrossRefGoogle Scholar
  70. Sofroniew MV, Isacson O (1988) Distribution of degeneration of cholinergic neurons in the septum following axotomy in different portions of the fimbria-fornix: a correlation between cell loss and proximity to the lesion. J Chem Neuroant 1:327–337.Google Scholar
  71. Takeuchi R, Murase K, Furukawa Y, Furukawa S, Hayashi K (1990) Stimulation of nerve growth factor synthesis/secretion by 1, 4-benzoquinone and its derivatives in cultured mouse astroglial cells. FEBS Lett 261(1):63–66.PubMedCrossRefGoogle Scholar
  72. Thoenen H, Bandtlow C, Heumann R (1987) The physiological function of nerve growth factor in the central nervous system: comparison with the periphery. Rev Physiol Biochem Pharmacol 109:145–178.PubMedCrossRefGoogle Scholar
  73. Toran-Allerand CD, Miranda RC, Bentham WDL, Shrabji F, Brown TJ, Hochberg RB, MacLusky NJ (1992) Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proc Natl Acad Sci USA 89:4668–4672.PubMedCrossRefGoogle Scholar
  74. Touchette N (1993) Rising spirits for motor neuron revival. J NIH Res 5:53–59.Google Scholar
  75. Tuszynski Mhuhs, Yoshida K, Gage FH (1991) Recombinant human nerve growth factor infusions prevent cholinergic neuronal degeneration in the adult primate brain. Ann Neurol 30:625–636.CrossRefGoogle Scholar
  76. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, De Long MR (1982) Alzheimer’s disease and senile dementia; loss of neurons in the basal forebrain. Science 215:1237–1239.PubMedCrossRefGoogle Scholar
  77. Williams LR (1991) Hypophagia is induced by intracerebroventricular administration of nerve growth factor. Exp Neurol 113:31–37.PubMedCrossRefGoogle Scholar
  78. Williams LR, Varon S, Peterson GM, Wictorin K, Fischer W, Bjorklund A, Gage FH (1986) Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection. Proc Natl Acad Sci USA 83:9231–9235.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1994

Authors and Affiliations

  • B. Knüsel
    • 1
  • F. Hefti
    • 1
  1. 1.Division of Neurogerontology, Andrus Gerontology CenterUniversity of Southern CaliforniaLos AngelesUSA

Personalised recommendations