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Nerve Growth Factor Expression and Function in the CNS

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Growth Factors and Alzheimer’s Disease

Part of the book series: Research and Perspectives in Alzheimer’s Disease ((ALZHEIMER))

Summary

Nerve growth factor (NGF) is a protein that is known to promote the survival, differentiation, and process extension of a number of neuronal systems to various degrees during development and, in some cases, in mature organisms. Deficits in the NGF responsiveness of basal forebrain cholinergic neurons may contribute to pathological changes in the aged central nervous system. One gene whose expression appears to be regulated by NGF is the amyloid protein precursor (APP), which encodes the β/A4 protein component of amyloid deposits in aged and Alzheimer’s diseased brain. In order to understand the regulation of APP gene expression by NGF in vivo, we have initiated studies in the basal forebrain of adult and aged rats using in situ hybridization and quantitative mRNA analysis of different APP transcripts, NGF receptor (NGFr) and choline acetyltransferase (ChAT) mRNAs. NGF or vehicle was infused into aged and young rats. In young adult rats, chronic NGF infusion produces robust increases in APP mRNA hybridization, NGFr mRNA hybridization, NGFr immunoreactivity, ChAT mRNA hybridization, and hypertrophy of ChAT immunoreactivity and mRNApositive neurons. NGF treatment also increases the ratio of APP-695 mRNA to APP-751 mRNA in the basal forebrain. Control aged rats with spatial memory deficits show increased levels of APP-751 mRNA in the forebrain as compared with aged nonimpaired or young control rats. We are currently examining whether NGF treatment in aged animals can effect changes in APP gene expression associated with behavioral impairment.

Lesion and aging studies in nonprimate mammalian models have shown that intracerebroventricular NGF infusions can prevent or reverse degenerative changes in central nervous system basal forebrain cholinergic neurons. Since some human neurodegenerative conditions result in the loss of basal forebrain cholinergic neurons, we sought to determine in a separate study whether lesion-induced damage to primate basal forebrain cholinergic neurons can be prevented by intracerebroventricular NGF infusions. Our results demonstrate that NGF substantially reduces lesion-induced cholinergic neuron degeneration in the nonhuman primate Macaca fascicularis. The use of neurotrophic therapy in human neurodegenerative studies requires a more complete understanding of actions of NGF on gene expression and functional measures in the rat and nonhuman primate.

Supported in part by grants from the NIA, NIH, NIMH, the Pew Foundation, the Margaret and Herbert Hoover Foundation, and the Bristol-Myers Squibb Company.

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References

  • Amaral DG, Kurz J (1985) An analysis of the origins of the cholinergie and noncholinergic septal projections to the hippocampal formation of the rat. J Comp Neurol 420: 37–59

    Article  Google Scholar 

  • Appel SH (1981) A unifying hypothesis for the cause of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer disease. Ann Neurol 10: 499–505

    Article  PubMed  CAS  Google Scholar 

  • Arendt T, Zvegintseva HG, Leontovich TA (1986) Dendritic changes in the basal nucleus of Meynert and in the diagonal band nucleus in Alzheimer’s disease — a quantitative golgi investigation. Neuroscience 19: 1265–1278

    Article  PubMed  CAS  Google Scholar 

  • Arendt T, Taubert G, Bigl V, Arendt A (1988) Amyloid deposition in the nucleus basalis of Meynert complex: a topographic marker for degenerating cell clusters in Alzheimer’s disease. Acta Neuropathol (Berl) 75: 226–232

    Article  CAS  Google Scholar 

  • Arimatsu Y, Miyamoto M, Tsukui H, Hatanaka H (1988) Nerve growth factor enhances survival of identified projection neurons in the rat septal and diagonal band regions in vitro. Soc Neurosci Abstr 14: 11–14

    Google Scholar 

  • Armstrong DM, Terry RD, Deteresa RM, Bruce G, Hersh LB, Gage FH (1987) Response of septal cholinergie neurons to axotomy. J Comp Neurol 264: 421–436

    Article  PubMed  CAS  Google Scholar 

  • Ayer-LeLievre CS, Ebendal T, Olson L, Seiger A (1983) Localization of NGF-like immunoreactivity in rat neurons tissue. Med Biol 61: 296–304

    PubMed  CAS  Google Scholar 

  • Bartus R, Dean RL, Beer C, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408–417

    Article  PubMed  CAS  Google Scholar 

  • Batchelor PE, Armstrong DM, Blaker SN, Gage FH (1989) Nerve growth factor receptor and choline acetyltransferase colocalization in neurons within the rat forebrain: response to fimbria-fornix transection. J Comp Neurol 284: 187–204

    Article  PubMed  CAS  Google Scholar 

  • Bernd P, Greene LA (1984) Association of 125 I-nerve growth factor with PC 12 pheochromocytoma cells. Evidence for internalization via high-affinity receptors only and for long term regulation by nerve growth factor. J Biol Chem 259: 15509–15516

    PubMed  CAS  Google Scholar 

  • Cohen ML, Golde TE, Usiak MF, Younkin LH, Younkin SG (1988) In situ hybridization of nucleus basalis neurons shows increased beta-amyloid mRNA in Alzheimer’s disease. Proc Natl Acad Sci USA 85: 1227–1231

    Article  PubMed  CAS  Google Scholar 

  • Collins F, Crutcher KA (1985) Neurotrophic activity in the adult rat hippocampal formation: regional distribution and increase after septal lesion. J Neurosci 5: 2809–2814

    PubMed  CAS  Google Scholar 

  • Collins F, Dawson A (1983) An effect of nerve growth factor on parasympathetic neurite outgrowth. Proc Natl Acad Sci USA 80: 2091–2094

    Article  PubMed  CAS  Google Scholar 

  • Coyle JT, Price PH, Delong MR (1983) Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 219: 1184–1189

    Article  PubMed  CAS  Google Scholar 

  • Eckenstein F (1988) Transient expression of NGF-receptor-like immunoreactivity in postnatal rat brain and spinal cord. Brain Res 446: 149–154

    Article  PubMed  CAS  Google Scholar 

  • Fischer W, Wictorin K, Bjorklund A, Williams LR, Varon S, Gage FH (1987) Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 329: 65–68

    Article  PubMed  CAS  Google Scholar 

  • Friedman PL, Larhammar D, Holets VR, Gonzalez-Cavajal M, Yu ZY, Persson H, Whittemore SR (1988) Rat 13-NGF sequence and sites of synthesis in adult CNS. Soc Neurosci Abstr 14: 8–27

    Google Scholar 

  • Furukawa S, Furukawa Y, Satoyoshi E, Hayashi K (1986) Synthesis and secretion of nerve growth factor by mouse astroglial cells in culture. Biochem Biophys Res Comm 136: 57–63

    Article  PubMed  CAS  Google Scholar 

  • Gage FH, Bjorklund A, Stenevi U, Dunnett SB (1983) Functional correlates of compensatory collateral sprouting by aminergic and cholinergic afferents in the hippocampal formation. Brain Res 268: 39–47

    Article  PubMed  CAS  Google Scholar 

  • Gage FH, Bjorklund A, Stenevi U (1984) Denervation releases a neuronal survival factor in adult rat hippocampus. Nature 308: 637–639

    Article  PubMed  CAS  Google Scholar 

  • Gage FH, Wictorin K, Ficher W, Williams LR, Varon S, Bjorklund A (1986) Retrograde cell changes in medial septum and diagonal band following fimbria-fornix transection: quantitative temporal analysis. Neuroscience 19: 241–255

    Article  PubMed  CAS  Google Scholar 

  • Gage FH, Armstrong DM, Williams LR, Varon S (1988) Morphologic response of axotomized septal neurons to nerve growth factor. J Comp Neurol 269: 147–155

    Article  PubMed  CAS  Google Scholar 

  • Gage FH, Batchelor P, Chen KS, Chin D, Higgins GA, Koh S, Deputy S, Rosenberg MB, Fischer W, Bjorklund A (1989) NGF receptor reexpression and NGF mediated cholinergic neuronal hypertrophy in the damaged adult neostriatum. Neuron 2: 1177–1184

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Pinilla F, Guthrie K, Leon M. Nieto-Sampedro M (1988) NGF receptor increase in the olfactory bulb after early odor deprivation in rats. Soc Neurosci Abstr 1: 685

    Google Scholar 

  • Grady S, Reeves T, Steward O (1984) Time course of retrograde degeneration of the cells of origin of the septohippocampal pathway after fimbria-fornix transections. Soc Neurosci Abstr 10: 463

    Google Scholar 

  • Greene LA (1977) Quantitative in vitro studies on the nerve growth factor requirement of neurons. I. Sympathetic neurons. Dev Biol 58: 96–105

    Article  PubMed  CAS  Google Scholar 

  • Hagg T, Manthorpe M, Vashlsing 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

    Article  PubMed  CAS  Google Scholar 

  • Hefti F (1983) Is Alzheimer’s disease caused by a lack of nerve growth factor? Ann Neurol 13: 109–110

    Article  PubMed  CAS  Google Scholar 

  • Hefti F (1986a) Nerve growth factor (NGF) promotes survival of septal cholinergic neurons after fimbrial transection. J Neurosci 6: 2155–2162

    CAS  Google Scholar 

  • Hefti F (1986b) Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 14: 2155–2162

    Google Scholar 

  • Hefti F, Dravid A, Hartikka JJ (1984) Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase activity in adult rats with partial septohippocampal lesions. J Brain Res 293: 305–311

    Article  CAS  Google Scholar 

  • Kao CC, Chang LW, Bloodworth MB (1977a) The mechanism of spinal cord cavitation following spinal cord transection. Part 2. J Neurosurg 46: 745–757

    Article  CAS  Google Scholar 

  • Kao CC, Chang LW, Bloodworth JMB (1977b) The mechanism of spinal cord cavitation following spinal cord transection. Part 3. J Neurosurg 46: 757–766

    Article  CAS  Google Scholar 

  • Kitaguchi N, Takahashi Y, Tokushima Y, Shiojiri S, Ito H (1988) Novel precursor of Alzheimer’s disease amyloid protein shows protease inhibitory activity. Nature 331: 530–532

    Article  PubMed  CAS  Google Scholar 

  • Koh S, Loy R (1988) Age-related loss of nerve growth factor sensitivity in rat basal forebrain neurons. Brain Res 440: 396–401

    Article  PubMed  CAS  Google Scholar 

  • Kromer LF (1987) Nerve growth factor treatment after brain injury prevents neuronal death. Science 235: 214–216

    Article  PubMed  CAS  Google Scholar 

  • Large TH, Bodary SC, Clegg DO, Weskamp G, Otten U, Reichardt LF (1986) Nerve growth factor gene expression in the developing rat brain. Science 234: 352–355

    Article  PubMed  CAS  Google Scholar 

  • Larkfors L, Ebendal T, Whittemore SR, Persson H, Hoffer B, Olson L (1987) Decreased level of nerve growth factor (NGF) and its messenger RNA in the aged rat brain. Mol Brain Res 3: 55–60

    Article  Google Scholar 

  • Lewis PR, Shute CCD, Silver A (1967) Confirmation from cholineacetylase of a massive cholinergic innervation to the rat hippocampus. J Physiol 191: 215–224

    PubMed  CAS  Google Scholar 

  • Luine VN, Renner KJ, Heady S, Jones KJ (1986) Age and sex-dependent decreases in ChAT in basal forebrain nuclei. Neurobiol Aging 7: 193–198

    Article  PubMed  CAS  Google Scholar 

  • Mobley WC, Rutkowski JL, Tennekoon GII, Buchanan K, Johnston MW (1985) Choline acetyltransferase activity in striatum of neonatal rats increased by nerve growth factor. Science 229: 284–287

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Montero CN, Hefti F (1988) Rescue of lesioned septal cholinergic neurons by nerve growth factor: specificity and requirement for chronic treatment. J Neurosci 8: 2986–2999

    PubMed  CAS  Google Scholar 

  • Nieto-Sampedro M, Manthorpe M, Barbin G, Varon S, Cotman CW (1983) Injury-induced neuronotrophic activity in adult rat brain: correlation with survival delayed implants in the wound cavity. J Neurosci 3: 2219–2229

    PubMed  CAS  Google Scholar 

  • Nygren L, Olson L, Seiger A (1971) Regeneration of monoamine-containing axons in the developing and adult spinal cord of the rat following intraspinal 6-OH-dopamine injections or transections. Histochemie 28: 1–15

    Article  PubMed  CAS  Google Scholar 

  • Palmert MR, Golde TE, Cohen ML, Kovacs M, Tanzi RE, Gusella JF, Younkin SG (1988) Amyloid protein precursor messenger RNAs: differential expression in Alzheimer’s disease. Science 241: 1080–1083

    Article  PubMed  CAS  Google Scholar 

  • Peterson GM, William LR, Varon S, Gage FH (1987) Loss of GABAergic neurons in the medial septum after fimbria-fornix transection. Neurosci Lett 76: 140–144

    Article  PubMed  CAS  Google Scholar 

  • Phelps CH, Gage FH, Growdon H, Hefti F, Harbaugh R, Johnston MV, Khachaturian ZS, Mobley WC, Price DL, Raskind M, Simpkins J, Thal LJ, Woodcock J (1989) Potential use of nerve growth factor to treat Alzheimer’s disease. Neurobiol Aging 10: 205–207

    Article  PubMed  CAS  Google Scholar 

  • Ponte P, Gonzalez-DeWhitt P, Schilling J, Miller J, Hsu D, Greenberg B, Davis K (1988) A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature 331: 525–527

    Article  PubMed  CAS  Google Scholar 

  • Richardson PM, Verge Isse VMK, Riopelle RJ (1986) Distribution of neuronal receptors for nerve growth factor in the rat. J Neurosci 6: 2312–2321

    PubMed  CAS  Google Scholar 

  • Rohrer H, Barde YA (1982) Presence and disappearance of nerve growth factor receptors on sensory neurons in culture. Dev Biol 89: 309–315

    Article  PubMed  CAS  Google Scholar 

  • Schwab ME, Otten U, Agid Y, Thoenen H (1979) Nerve growth factor (NGF) in the rat CNS: absence of specific retrograde axonal transport and tyrosine hydroxylase induction in locus coeruleus and substantia nigra. Brain Res 168: 473–483

    Article  PubMed  CAS  Google Scholar 

  • Scott SM, Tarris R, Eveleth D, Mansfield H, Weichsel ME, Fisher DA (1981) Bioassay detection of mouse nerve growth factor (mNGF) in the brain of adult mice. J Neurosci Res 6: 653–658

    Article  PubMed  CAS  Google Scholar 

  • Seiler M, Schwab ME (1984) Specific retrograde transport of nerve growth factor (NGF) from cortex to nucleus basalis in the rat. Brain Res 300: 33–39

    Article  PubMed  CAS  Google Scholar 

  • Sheldon DL, Reichardt LF (1986) Studies on the expression of the beta-nerve growth factor (NGF) gene in the central nervous system; level and regional distribution of NGF mRNA suggest that NGF functions as a trophic factor for several distinct populations of neurons. Proc Natl Acad Sci USA 83: 2714–2718

    Article  Google Scholar 

  • Taniuchi M, Johnson EM (1985) Characterization of the binding properties and retrograde axonal transport of monoclonal antibody directed against the rat nerve growth factor receptor. J Cell Biol 101: 1100–1106

    Article  PubMed  CAS  Google Scholar 

  • Taniuchi M, Schweizer JB, Johnson EM (1986) Nerve growth factor receptor molecules in rat brain. Proc Natl Acad Sci USA 83: 1950–1954

    Article  PubMed  CAS  Google Scholar 

  • Tanzi R, McClatchey AI, Lamperti ED, Villa-Komaroff L, Gusella JF, Neve RL (1988) Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer’s disease. Nature 331: 528–530

    Article  PubMed  CAS  Google Scholar 

  • Thoenen H, Barde YA (1980) Physiology of nerve growth factor. Physiol Rev 60: 1284–1335

    PubMed  CAS  Google Scholar 

  • Tuszynski MH, Amaral DG, U H-S, Yoshida K, Gage FH (1989) Intracerebroventricular NGF infusions prevent retrograde cholinergic neuron degeneration in the primate. Soc Neurosci Abst 15: 707–707

    Google Scholar 

  • Tuszynski MH, Armstrong DM, Gage FH (1990) Basal forebrain cell loss following fimbriafornix transection. Brain Res 508: 241–248

    Article  PubMed  CAS  Google Scholar 

  • Wainer BH, Levey AI, Rye DB, Mesulam M, Mufson EJ (1985) Cholinergic and non-cholinergic septohippocampal pathways. Neurosci Lett 54: 45–52

    Article  PubMed  CAS  Google Scholar 

  • Whittemore SR, Ebendal T, Larkfors L, Olson L, Seiger A, Stromberg I, Persson H (1986) Developmental and regional expression of 13 nerve growth factor messenger RNA and protein in the rat central nervous system. Proc Natl Acad Sci USA 83: 817–821

    Article  PubMed  CAS  Google Scholar 

  • Williams LR, Varon S, Peterson GM, Wictorin K, Fisher 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

    Article  PubMed  CAS  Google Scholar 

  • Yan Q, Johnson EM (1988) An immunohistochemical study of the nerve growth factor receptor in developing rats. J Neurosci 8: 3481–3498

    PubMed  CAS  Google Scholar 

  • Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science 245: 417–420

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. F. H. Gage
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  2. M. Tuszynski
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  3. K. Yoshida
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  4. G. Higgins
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Editor information

Editors and Affiliations

  1. Andrus Gerontology Center, University of Southern California, 90089, Los Angeles, CA, USA

    Franz Hefti Ph. D.

  2. INSERM U 298, Centre Hospitalier Régional et Universitaire, F-49033, Angers Cedex, France

    Philippe Brachet Ph. D.

  3. Département de Neurophysiologie et de Biologie des Comportements, Centre de Neurochimie du C.N.R.S., 12 rue Goethe, F-67000, Strasbourg, France

    Bruno Will Ph. D.

  4. Fondation IPSEN pour la Recherche Thérapeutique, 30, rue Cambronne, F-75737, Paris Cedex, France

    Yves Christen Ph. D.

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© 1991 Springer-Verlag Berlin Heidelberg

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Gage, F.H., Tuszynski, M., Yoshida, K., Higgins, G. (1991). Nerve Growth Factor Expression and Function in the CNS. In: Hefti, F., Brachet, P., Will, B., Christen, Y. (eds) Growth Factors and Alzheimer’s Disease. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-46722-6_10

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  • DOI: https://doi.org/10.1007/978-3-642-46722-6_10

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-46724-0

  • Online ISBN: 978-3-642-46722-6

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