Cellular and Molecular Neurobiology

, Volume 26, Issue 4–6, pp 617–631 | Cite as

On the Molecular Basis Linking Nerve Growth Factor (NGF) to Alzheimer’s Disease



1. Alzheimer’s disease (AD) is pathologically defined by the deposition of amyloid peptide and neurofibrillary tangles and is characterized by a progressive loss of cognition and memory function, due to marked cortical cholinergic depletion.

2. Cholinergic cortical innervation is provided by basal forebrain cholinergic neurons. The neurotrophin Nerve Growth Factor (NGF) promotes survival and differentiation of basal forebrain cholinergic neurons.

3. This assertion has been at the basis of the hypothesis developed in the last 20 years, whereby NGF deprivation would be one of the factor involved in the etiology of sporadic forms of AD.

4. In this review, we shall summarize data that lead to the production and characterization of a mouse model for AD (AD11 anti-NGF mice), based on the expression of transgenic antibodies neutralizing NGF. The AD-like phenotype of AD11 mice will be discussed on the basis of recent studies that have posed NGF and its precursor pro-NGF back to the stage of AD-like neurodegeneration, showing the involvement of the precursor pro-NGF in one of the cascades leading to AD neurodegeneration.


Alzheimer’s disease nerve growth factor TrkA P75NTR sortilin transgenic mice neurodegeneration 



The authors are grateful to Dr. Piero Giulio Giulianini (University of Trieste) for performing electron microscopy analysis of AD11 brain extracts and to Dr. Gabriele Ugolini for helpful discussions and Mrs. Lucia de Caprio for reading the manuscript.


  1. Alonso, A. D., Grundke-Iqbal, I., Barra, H. S., and Iqbal, K. (1997). Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: Sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc. Natl. Acad. Sci. U. S. A. 94:298–303.CrossRefGoogle Scholar
  2. Baldwin, A. N., Bitler, C. M., Welcher, A. A., and Shooter, E. M. (1992). Studies on the structure and binding properties of the cysteine-rich domain of rat low affinity nerve growth factor receptor (p75NGFR). J. Biol. Chem. 267:8352–8359.Google Scholar
  3. Bartus, R. T., Dean, R. L., 3rd, Beer, B., and Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414.CrossRefGoogle Scholar
  4. Binder, L. I., Guillozet-Bongaarts, A. L., Garcia-Sierra, F., and Berry, R. W. (2005). Tau, tangles, and Alzheimer’s disease. Biochim. Biophys. Acta 1739:216–223.Google Scholar
  5. Blesch, A., and Tuszynski, M. H. (2004). Gene therapy and cell transplantation for Alzheimer’s disease and spinal cord injury. Yonsei. Med. J. 45(Suppl):28–31.Google Scholar
  6. Boissiere, F., Hunot, S., Faucheux, B., Hersh, L. B., Agid, Y., and Hirsch, E. C. (1997). Trk neurotrophin receptors in cholinergic neurons of patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 8:1–8.Google Scholar
  7. Braak, H., and Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta. Neuropathol. (Berl.) 82:239–259.CrossRefGoogle Scholar
  8. Capsoni, S., Giannotta, S., and Cattaneo, A. (2002a). Beta-amyloid plaques in a model for sporadic Alzheimer’s disease based on transgenic anti-nerve growth factor antibodies. Mol. Cell. Neurosci. 21:15–28.CrossRefGoogle Scholar
  9. Capsoni, S., Giannotta, S., and Cattaneo, A. (2002b). Early events of Alzheimer-like neurodegeneration in anti-nerve growth factor transgenic mice. Brain. Aging 2:24–43.Google Scholar
  10. Capsoni, S., Giannotta, S., and Cattaneo, A. (2002c). Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice. Proc. Natl. Acad. Sci. U. S. A. 99:12432–12437.CrossRefGoogle Scholar
  11. Capsoni, S., Giannotta, S., Stebel, M., Garcia, A. A., De Rosa, R., Villetti, G., Imbimbo, B. P., Pietra, C., and Cattaneo, A. (2004). Ganstigmine and donepezil improve neurodegeneration in AD11 antinerve growth factor transgenic mice. Am. J. Alzheimers Dis. Other Demen. 19:153–160.CrossRefGoogle Scholar
  12. Capsoni, S., Ruberti, F., Di Daniel, E., and Cattaneo, A. (2000a). Muscular dystrophy in adult and aged anti-NGF transgenic mice resembles an inclusion body myopathy. J. Neurosci. Res. 59:553–560.CrossRefGoogle Scholar
  13. Capsoni, S., Ugolini, G., Comparini, A., Ruberti, F., Berardi, N., and Cattaneo, A. (2000b). Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc. Natl. Acad. Sci. U. S. A. 97:6826–6831.CrossRefGoogle Scholar
  14. Cattaneo, A. (1998). Selection of intracellular antibodies. Bratisl. Lek. Listy. 99:413–418.Google Scholar
  15. Cattaneo, A., and Neuberger, M. S. (1987). Polymeric immunoglobulin M is secreted by transfectants of non-lymphoid cells in the absence of immunoglobulin J chain. EMBO J. 6:2753–2758.Google Scholar
  16. Cattaneo, A., Rapposelli, B., and Calissano, P. (1988). Three distinct types of monoclonal antibodies after long-term immunization of rats with mouse nerve growth factor. J. Neurochem. 50:1003–1010.CrossRefGoogle Scholar
  17. Chao, M. V., Bothwell, M. A., Ross, A. H., Koprowski, H., Lanahan, A. A., Buck, C. R., and Sehgal, A. (1986). Gene transfer and molecular cloning of the human NGF receptor. Science 232:518–521.CrossRefGoogle Scholar
  18. Chapman, B. S., and Kuntz, I. D. (1995). Modeled structure of the 75-kDa neurotrophin receptor. Protein Sci. 4:1696–1707.CrossRefGoogle Scholar
  19. Chen, K. S., Nishimura, M. C., Armanini, M. P., Crowley, C., Spencer, S. D., and Phillips, H. S. (1997). Disruption of a single allele of the nerve growth factor gene results in atrophy of basal forebrain cholinergic neurons and memory deficits. J. Neurosci. 17:7288–7296.Google Scholar
  20. Chen, X. Q., Fawcett, J. R., Rahman, Y. E., Ala, T. A., and Frey, I. W. (1998). Delivery of nerve growth factor to the brain via the olfactory pathway. J. Alzheimers Dis. 1:35–44.Google Scholar
  21. Cohen, S. (1959). Purification and metabolic effects of a nerve growth-promoting protein from snake venom. J. Biol. Chem. 234:1129–1137.Google Scholar
  22. Collerton, D. (1986). Cholinergic function and intellectual decline in Alzheimer’s disease. Neuroscience 19:1–28.CrossRefGoogle Scholar
  23. Cordon-Cardo, C., Tapley, P., Jing, S. Q., Nanduri, V., O’Rourke, E., Lamballe, F., Kovary, K., Klein, R., Jones, K. R., Reichardt, L. F. et al. (1991). The trk tyrosine protein kinase mediates the mitogenic properties of nerve growth factor and neurotrophin-3. Cell 66:173–183.CrossRefGoogle Scholar
  24. Counts, S. E., Nadeem, M., Wuu, J., Ginsberg, S. D., Saragovi, H. U., and Mufson, E. J. (2004). Reduction of cortical TrkA but not p75(NTR) protein in early-stage Alzheimer’s disease. Ann. Neurol. 56:520–531.CrossRefGoogle Scholar
  25. Crowley, C., Spencer, S. D., Nishimura, M. C., Chen, K. S., Pitts-Meek, S., Armanini, M. P., Ling, L. H., MacMahon, S. B., Shelton, D. L., Levinson, A. D. et al. (1994). Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76:1001–1011.CrossRefGoogle Scholar
  26. Crutcher, K. A., Scott, S. A., Liang, S., Everson, W. V., and Weingartner, J. (1993). Detection of NGF-like activity in human brain tissue: Increased levels in Alzheimer’s disease. J. Neurosci. 13:2540–2550.Google Scholar
  27. Cunningham, M. E., Stephens, R. M., Kaplan, D. R., and Greene, L. A. (1997). Autophosphorylation of activation loop tyrosines regulates signaling by the TRK nerve growth factor receptor. J. Biol. Chem. 272:10957–10967.CrossRefGoogle Scholar
  28. De Rosa, R., Garcia, A., Braschi, C., Capsoni, S., Maffei, L., Berardi, N., and Cattaneo, A. (2005). Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc. Natl. Acad. Sci. U. S. A. 102:3811–3816.CrossRefGoogle Scholar
  29. DeKosky, S. T., Harbaugh, R. E., Schmitt, F. A., Bakay, R. A., Chui, H. C., Knopman, D. S., Reeder, T. M., Shetter, A. G., Senter, H. J., and Markesbery, W. R. (1992). Cortical biopsy in Alzheimer’s disease: Diagnostic accuracy and neurochemical, neuropathological, and cognitive correlations. Intraventricular Bethanecol Study Group. Ann. Neurol. 32:625–632.CrossRefGoogle Scholar
  30. Fahnestock, M., Michalski, B., Xu, B., and Coughlin, M. D. (2001). The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer’s disease. Mol. Cell. Neurosci. 18:210–220.CrossRefGoogle Scholar
  31. Fahnestock, M., Scott, S. A., Jette, N., Weingartner, J. A., and Crutcher, K. A. (1996). Nerve growth factor mRNA and protein levels measured in the same tissue from normal and Alzheimer’s disease parietal cortex. Brain Res. Mol. Brain Res. 42:175–178.CrossRefGoogle Scholar
  32. Fischer, W., Wictorin, K., Bjorklund, A., Williams, L. R., Varon, S., and Gage, F. H. (1987). Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 329:65–68.CrossRefGoogle Scholar
  33. Frey, I. W. H., Liu, J., Chen, X. Q., Thorne, R. G., Fawcett, J. R., Ala, T. A., and Rahman, Y. E. (1997). Delivery of 125I-NGF to the brain via the olfactory route. Drug Deliv. 4:87–92.Google Scholar
  34. Golde, T. E. (2005). The Abeta hypothesis: Leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease. Brain Pathol. 15:84–87.CrossRefGoogle Scholar
  35. Harrington, A. W., Leiner, B., Blechschmitt, C., Arevalo, J. C., Lee, R., Morl, K., Meyer, M., Hempstead, B. L., Yoon, S. O., and Giehl, K. M. (2004). Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury. Proc. Natl. Acad. Sci. U. S. A. 101:6226–6230.CrossRefGoogle Scholar
  36. He, X. L., and Garcia, K. C. (2004). Structure of nerve growth factor complexed with the shared neurotrophin receptor p75. Science 304:870–875.CrossRefGoogle Scholar
  37. Hefti, F., Knusel, B., and Lapchak, P. A. (1993). Protective effects of nerve growth factor and brain-derived neurotrophic factor on basal forebrain cholinergic neurons in adult rats with partial fimbrial transections. Prog. Brain Res. 98:257–263.Google Scholar
  38. Hellweg, R., Gericke, C. A., Jendroska, K., Hartung, H. D., and Cervos-Navarro, J. (1998). NGF content in the cerebral cortex of non-demented patients with amyloid-plaques and in symptomatic Alzheimer’s disease. Int. J. Dev. Neurosci. 16:787–794.CrossRefGoogle Scholar
  39. Hempstead, B. L., Martin-Zanca, D., Kaplan, D. R., Parada, L. F., and Chao, M. V. (1991). High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350:678–683.CrossRefGoogle Scholar
  40. Hock, C., Heese, K., Hulette, C., Rosenberg, C., and Otten, U. (2000). Region-specific neurotrophin imbalances in Alzheimer disease: Decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch. Neurol. 57:846–851.CrossRefGoogle Scholar
  41. Hock, C., Heese, K., Muller-Spahn, F., Hulette, C., Rosenberg, C., and Otten, U. (1998). Decreased trkA neurotrophin receptor expression in the parietal cortex of patients with Alzheimer’s disease. Neurosci. Lett. 241:151–154.CrossRefGoogle Scholar
  42. Holtzman, D. M., Li, Y., Chen, K., Gage, F. H., Epstein, C. J., and Mobley, W. C. (1993). Nerve growth factor reverses neuronal atrophy in a Down syndrome model of age-related neurodegeneration. Neurology 43:2668–2673.Google Scholar
  43. Huang, E. J., and Reichardt, L. F. (2003). Trk receptors: Roles in neuronal signal transduction. Annu. Rev. Biochem. 72:609–642.CrossRefGoogle Scholar
  44. Ibanez, C. F., Ebendal, T., and Persson, H. (1991). Chimeric molecules with multiple neurotrophic activities reveal structural elements determining the specificities of NGF and BDNF. EMBO J. 10:2105–2110.Google Scholar
  45. Iqbal, K., Alonso Adel, C., Chen, S., Chohan, M. O., El-Akkad, E., Gong, C. X., Khatoon, S., Li, B., Liu, F., Rahman, A., Tanimukai, H., and Grundke-Iqbal, I. (2005). Tau pathology in Alzheimer disease and other tauopathies. Biochim. Biophys. Acta 1739:198–210.Google Scholar
  46. Jing, S., Tapley, P., and Barbacid, M. (1992). Nerve growth factor mediates signal transduction through trk homodimer receptors. Neuron 9:1067–1079.CrossRefGoogle Scholar
  47. Johnson, D., Lanahan, A., Buck, C. R., Sehgal, A., Morgan, C., Mercer, E., Bothwell, M., and Chao, M. (1986). Expression and structure of the human NGF receptor. Cell 47:545–554.CrossRefGoogle Scholar
  48. Kaplan, D. R., Martin-Zanca, D., and Parada, L. F. (1991). Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature 350:158–160.CrossRefGoogle Scholar
  49. Kaplan, D. R., and Miller, F. D. (2000). Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10:381–391.CrossRefGoogle Scholar
  50. Klein, R., Jing, S. Q., Nanduri, V., O’Rourke, E., and Barbacid, M. (1991). The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 65:189–197.CrossRefGoogle Scholar
  51. Koliatsos, V. E., Applegate, M. D., Knusel, B., Junard, E. O., Burton, L. E., Mobley, W. C., Hefti, F. F., and Price, D. L. (1991a). Recombinant human nerve growth factor prevents retrograde degeneration of axotomized basal forebrain cholinergic neurons in the rat. Exp. Neurol. 112:161–173.CrossRefGoogle Scholar
  52. Koliatsos, V. E., Clatterbuck, R. E., Nauta, H. J., Knusel, B., Burton, L. E., Hefti, F. F., Mobley, W. C., and Price, D. L. (1991b). Human nerve growth factor prevents degeneration of basal forebrain cholinergic neurons in primates. Ann. Neurol. 30:831–840.CrossRefGoogle Scholar
  53. Koliatsos, V. E., Nauta, H. J., Clatterbuck, R. E., Holtzman, D. M., Mobley, W. C., and Price, D. L. (1990). Mouse nerve growth factor prevents degeneration of axotomized basal forebrain cholinergic neurons in the monkey. J. Neurosci. 10:3801–3813.Google Scholar
  54. Lee, K. F., Li, E., Huber, L. J., Landis, S. C., Sharpe, A. H., Chao, M. V., and Jaenisch, R. (1992). Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69:737–749.CrossRefGoogle Scholar
  55. Lee, R., Kermani, P., Teng, K. K., and Hempstead, B. L. (2001). Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948.CrossRefGoogle Scholar
  56. Levi-Montalcini, R., and Hamburger, V. (1951). Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J. Exp. Zool. 116:321–361.CrossRefGoogle Scholar
  57. Li, Y., Holtzman, D. M., Kromer, L. F., Kaplan, D. R., Chua-Couzens, J., Clary, D. O., Knusel, B., and Mobley, W. C. (1995). Regulation of TrkA and ChAT expression in developing rat basal forebrain: Evidence that both exogenous and endogenous NGF regulate differentiation of cholinergic neurons. J. Neurosci. 15:2888–2905.Google Scholar
  58. Mandelkow, E. M., Schweers, O., Drewes, G., Biernat, J., Gustke, N., Trinczek, B., and Mandelkow, E. (1996). Structure, microtubule interactions, and phosphorylation of tau protein. Ann. N. Y. Acad. Sci. 777:96–106.Google Scholar
  59. Markowska, A. L., Koliatsos, V. E., Breckler, S. J., Price, D. L., and Olton, D. S. (1994). Human nerve growth factor improves spatial memory in aged but not in young rats. J. Neurosci. 14:4815–4824.Google Scholar
  60. Markowska, A. L., Price, D., and Koliatsos, V. E. (1996). Selective effects of nerve growth factor on spatial recent memory as assessed by a delayed nonmatching-to-position task in the water maze. J. Neurosci. 16:3541–3548.Google Scholar
  61. Mobley, W. C., Rutkowski, J. L., Tennekoon, G. I., Gemski, J., Buchanan, K., and Johnston, M. V. (1986). Nerve growth factor increases choline acetyltransferase activity in developing basal forebrain neurons. Brain Res. 387:53–62.Google Scholar
  62. Molnar, M., Ruberti, F., Cozzari, C., Domenici, L., and Cattaneo, A. (1997). A critical period in the sensitivity of basal forebrain cholinergic neurones to NGF deprivation. Neuroreport 8:575–579.Google Scholar
  63. Molnar, M., Tongiorgi, E., Avignone, E., Gonfloni, S., Ruberti, F., Domenici, L., and Cattaneo, A. (1998). The effects of anti-nerve growth factor monoclonal antibodies on developing basal forebrain neurons are transient and reversible. Eur. J. Neurosci. 10:3127–3140.CrossRefGoogle Scholar
  64. Mowla, S. J., Pareek, S., Farhadi, H. F., Petrecca, K., Fawcett, J. P., Seidah, N. G., Morris, S. J., Sossin, W. S., and Murphy, R. A. (1999). Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J. Neurosci. 19:2069–2080.Google Scholar
  65. Mufson, E. J., Conner, J. M., and Kordower, J. H. (1995). Nerve growth factor in Alzheimer’s disease: Defective retrograde transport to nucleus basalis. Neuroreport 6:1063–1066.Google Scholar
  66. Mufson, E. J., Conner, J. M., Varon, S., and Kordower, J. H. (1994). Nerve growth factor-like immunoreactive profiles in the primate basal forebrain and hippocampal formation. J. Comp. Neurol. 341:507–519.CrossRefGoogle Scholar
  67. Mufson, E. J., Kroin, J. S., Sendera, T. J., and Sobreviela, T. (1999). Distribution and retrograde transport of trophic factors in the central nervous system: Functional implications for the treatment of neurodegenerative diseases. Prog. Neurobiol. 57:451–484.CrossRefGoogle Scholar
  68. Mufson, E. J., Lavine, N., Jaffar, S., Kordower, J. H., Quirion, R., and Saragovi, H. U. (1997). Reduction in p140-TrkA receptor protein within the nucleus basalis and cortex in Alzheimer’s disease. Exp. Neurol. 146:91–103.CrossRefGoogle Scholar
  69. Mufson, E. J., Li, J. M., Sobreviela, T., and Kordower, J. H. (1996). Decreased trkA gene expression within basal forebrain neurons in Alzheimer’s disease. Neuroreport 8:25–29.Google Scholar
  70. Mufson, E. J., Ma, S. Y., Cochran, E. J., Bennett, D. A., Beckett, L. A., Jaffar, S., Saragovi, H. U., and Kordower, J. H. (2000). Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer’s disease. J. Comp. Neurol. 427:19–30.CrossRefGoogle Scholar
  71. Nykjaer, A., Lee, R., Teng, K. K., Jansen, P., Madsen, P., Nielsen, M. S., Jacobsen, C., Kliemannel, M., Schwarz, E., Willnow, T. E., Hempstead, B. L., and Petersen, C. M. (2004). Sortilin is essential for proNGF-induced neuronal cell death. Nature 427:843–848.CrossRefGoogle Scholar
  72. Perry, E. K., Tomlinson, B. E., Blessed, G., Bergmann, K., Gibson, P. H., and Perry, R. H. (1978). Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br. Med. J. 2:1457–1459.CrossRefGoogle Scholar
  73. Pesavento, E., Capsoni, S., Domenici, L., and Cattaneo, A. (2002). Acute cholinergic rescue of synaptic plasticity in the neurodegenerating cortex of anti-nerve-growth-factor mice. Eur. J. Neurosci. 15:1030–1036.CrossRefGoogle Scholar
  74. Piccioli, P., Di Luzio, A., Amann, R., Schuligoi, R., Surani, M. A., Donnerer, J., and Cattaneo, A. (1995). Neuroantibodies: ectopic expression of a recombinant anti-substance P antibody in the central nervous system of transgenic mice. Neuron 15:373–384.CrossRefGoogle Scholar
  75. Rodriguez-Tebar, A., Dechant, G., and Barde, Y. A. (1990). Binding of brain-derived neurotrophic factor to the nerve growth factor receptor. Neuron 4:487–492.CrossRefGoogle Scholar
  76. Roux, P. P., and Barker, P. A. (2002). Neurotrophin signaling through the p75 neurotrophin receptor. Prog. Neurobiol. 67:203–233.CrossRefGoogle Scholar
  77. Ruberti, F., Bradbury, A., and Cattaneo, A. (1993). Cloning and expression of an anti-nerve grwoth factor (NGF) antibody for studies using the neuroantibody approach. Cell. Mol. Neurobiol. 13:559–568.CrossRefGoogle Scholar
  78. Ruberti, F., Capsoni, S., Comparini, A., Di Daniel, E., Franzot, J., Gonfloni, S., Rossi, G., Berardi, N., and Cattaneo, A. (2000). Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe deficits in basal forebrain cholinergic neurons, cell death in the spleen, and skeletal muscle dystrophy. J. Neurosci. 20:2589–2601.Google Scholar
  79. Salehi, A., Delcroix, J. D., and Mobley, W. C. (2003). Traffic at the intersection of neurotrophic factor signaling and neurodegeneration. Trends. Neurosci. 26:73–80.CrossRefGoogle Scholar
  80. Scott, J., Selby, M., Urdea, M., Quiroga, M., Bell, G. I., and Rutter, W. J. (1983). Isolation and nucleotide sequence of a cDNA encoding the precursor of mouse nerve growth factor. Nature 302:538–540.CrossRefGoogle Scholar
  81. Scott, S. A., Mufson, E. J., Weingartner, J. A., Skau, K. A., and Crutcher, K. A. (1995). Nerve growth factor in Alzheimer’s disease: Increased levels throughout the brain coupled with declines in nucleus basalis. J. Neurosci. 15:6213–6221.Google Scholar
  82. Seidah, N. G., Benjannet, S., Pareek, S., Savaria, D., Hamelin, J., Goulet, B., Laliberte, J., Lazure, C., Chretien, M., and Murphy, R. A. (1996). Cellular processing of the nerve growth factor precursor by the mammalian pro-protein convertases. Biochem. J. 314(Pt. 3):951–960.Google Scholar
  83. Selkoe, D. J. (2001). Alzheimer’s disease: Genes, proteins, and therapy. Physiol. Rev. 81:741–766.Google Scholar
  84. Selkoe, D. J. (2002). Alzheimer’s disease is a synaptic failure. Science 298:789–791.CrossRefGoogle Scholar
  85. Shamovsky, I. L., Ross, G. M., Riopelle, R. J., and Weaver, D. F. (1999). The interaction of neurotrophins with the p75NTR common neurotrophin receptor: A comprehensive molecular modeling study. Protein Sci. 8:2223–2233.Google Scholar
  86. Shooter, E. M. (2001). Early days of the nerve growth factor proteins. Annu. Rev. Neurosci. 24:601–629.CrossRefGoogle Scholar
  87. Smith, D. E., Roberts, J., Gage, F. H., and Tuszynski, M. H. (1999). Age-associated neuronal atrophy occurs in the primate brain and is reversible by growth factor gene therapy. Proc. Natl. Acad. Sci. U. S. A. 96:10893–10898.CrossRefGoogle Scholar
  88. Squinto, S. P., Stitt, T. N., Aldrich, T. H., Davis, S., Bianco, S. M., Radziejewski, C., Glass, D. J., Masiakowski, P., Furth, M. E., Valenzuela, D. M. et al. (1991). trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor. Cell 65:885–893.CrossRefGoogle Scholar
  89. Stach, R. W., and Shooter, E. M. (1974). The biological activity of cross-linked beta nerve growth factor protein. J. Biol. Chem. 249:6668–6674.Google Scholar
  90. Ullrich, A., Gray, A., Berman, C., and Dull, T. J. (1983). Human beta-nerve growth factor gene sequence highly homologous to that of mouse. Nature 303:821–825.CrossRefGoogle Scholar
  91. Whitehouse, P. J., Price, D. L., Struble, R. G., Clark, A. W., Coyle, J. T., and Delon, M. R. (1982). Alzheimer’s disease and senile dementia: Loss of neurons in the basal forebrain. Science 215:1237–1239.CrossRefGoogle Scholar
  92. Yan, H., and Chao, M. V. (1991). Disruption of cysteine-rich repeats of the p75 nerve growth factor receptor leads to loss of ligand binding. J. Biol. Chem. 266:12099–12104.Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Lay Line Genomics S.p.A.RomeItaly
  2. 2.European Brain Research Institute (EBRI)RomeItaly

Personalised recommendations