Skip to main content

Advertisement

SpringerLink
Log in

Gangliosides, NGF, Brain Aging and Disease: A Mini-Review with Personal Reflections

  • Overview
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

In this mini-review I summarize our research efforts in ascertaining the possible neuro-reparative properties of the GM1 ganglioside and its cooperative effects with NGF in stroke-lesion models. We also review aspects of our NGF investigations which have recently led to the discovery that NGF is released in an activity-dependent manner in the form of its precursor molecule, proNGF. These studies support the notion that in the CNS NGF metabolism conversion and degradation occur in the extracellular milieu. We have also validated this pathway in vivo demonstrating that the pharmacological inhibition of the pro-to mature NGF conversion results in the brain accumulation of proNGF and loss and atrophy of cortical cholinergic synapses. Furthermore, we have gathered neurochemical evidence for a compromise of this newly discovered NGF metabolic pathway in Alzheimer’s disease, explaining the vulnerability of NGF-dependent forebrain cholinergic neurons in this disease despite normal NGF synthesis and abundance of NGF precursor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Gorio A, Carmignoto G, Facci L, Finesso M (1980) Motor nerve sprouting induced by ganglioside treatment. Possible implications for gangliosides on neuronal growth. Brain Res 197(1):236–241

    Article  PubMed  CAS  Google Scholar 

  2. Pedata F, Giovannelli L, Pepeu G (1984) GM1 ganglioside facilitates the recovery of high affinity choline uptake in the cerebral cortex of rats with a lesion on the nucleus basalis magnocellularis. J Neurosci Res 12(2–3):421–427

    Article  PubMed  CAS  Google Scholar 

  3. Casamenti F, Bracco L, Bartolini L, Pepeu G (1985) Effects of ganglioside treatment in rats with a lesion of the cholinergic forebrain nuclei. Brain Res 338(1):45–52

    Article  PubMed  CAS  Google Scholar 

  4. Sofroniew MV, Pearson RC, Eckenstein F, Cuello AC, Powell TP (1983) Retrograde changes in cholinergic neurons in the basal forebrain of the rat following cortical damage. Brain Res 289(1–2):370–374

    Article  PubMed  CAS  Google Scholar 

  5. Sofroniew MV, Pearson RC, Cuello AC, Tagari PC, Stephens PH (1986) Parenterally administered GM1 ganglioside prevents retrograde degeneration of cholinergic cells of the rat basal forebrain. Brain Res 398(2):393–396

    Article  PubMed  CAS  Google Scholar 

  6. Garofalo L, Ribeiro-da-Silva A, Cuello AC (1993) Potentiation of nerve growth factor-induced alterations in cholinergic fibre length and presynaptic terminal size in cortex of lesioned rats by the monosialoganglioside GM1. Neuroscience 57(1):21–40

    Article  PubMed  CAS  Google Scholar 

  7. Garofalo L, Cuello AC (1994) Nerve growth factor and the monosialoganglioside GM1: analogous and different in vivo effects on biochemical, morphological, and behavioral parameters of adult cortically lesioned rats. Exp Neurol 125(2):195–217

    Article  PubMed  CAS  Google Scholar 

  8. Ledeen RWJ (1984) Biology of gangliosides: neuritogenic and neuronotrophic properties. Neurosci Res 12(2–3):147–159

    CAS  Google Scholar 

  9. Cannella MS, Oderfeld-Nowak B, Gradkowska M, Skup M, Garofalo L, Cuello AC, Ledeen RW (1990) Derivatives of ganglioside GM1 as neuronotrophic agents: comparison of in vivo and in vitro effects. Brain Res 513(2):286–294

    Article  PubMed  CAS  Google Scholar 

  10. Ledeen RW, Wu G, Cannella MS, Oderfeld-Nowak B, Cuello AC (1990) Gangliosides as neurotrophic agents: studies on the mechanism of action. Acta Neurobiol Exp (Wars) 50(4–5):439–449

    CAS  Google Scholar 

  11. Cuello AC (1990) Glycosphingolipids that can regulate nerve growth and repair. Adv Pharmacol 21:1–50

    Article  PubMed  CAS  Google Scholar 

  12. Levi-Montalcini R, Aloe L (1985) Differentiating effects of murine nerve growth factor in the peripheral and central nervous systems of Xenopus laevis tadpoles. Proc Nat Acad Sci USA 82(20):7111–7115

    Article  PubMed  CAS  Google Scholar 

  13. Cuello AC, Garofalo L, Kenigsberg RL, Maysinger D (1989) Gangliosides potentiate in vivo and in vitro effects of nerve growth factor on central cholinergic neurons. Proc Natl Acad Sci USA 86(6):2056–2060

    Article  PubMed  CAS  Google Scholar 

  14. Cuello AC, Garofalo L, Maysinger D (1990) Evidence for nerve growth factor-ganglioside interaction in forebrain cholinergic neurons. ACTA Neurobiol 50:451–460

    CAS  Google Scholar 

  15. Cuello AC, Maysinger D, Garofalo L (1992) Trophic factor effects on cholinergic innervation in the cerebral cortex of the adult rat brain. Mol Neurobiol 6(4):451–461

    Article  PubMed  CAS  Google Scholar 

  16. Maysinger D, Filipovic-Grcic J, Cuello AC (1993) Effects of coencapsulated NGF and GM1 in rats with cortical lesions. NeuroReport 4(7):971–974

    Article  PubMed  CAS  Google Scholar 

  17. Maysinger D, Garofalo L, Jalsenjak I, Cuello AC (1989) Effects of microencapsulated monosialoganglioside GM1 on cholinergic neurons. Brain Res 496(1–2):165–172

    Article  PubMed  CAS  Google Scholar 

  18. Garofalo L, Cuello AC (1995) Pharmacological characterization of nerve growth factor and/or monosialoganglioside GM1 effects on cholinergic markers in the adult lesioned brain. J Pharmacol Exp Ther 272(2):527–545

    PubMed  CAS  Google Scholar 

  19. Garofalo L, Ribeiro-da-Silva A, Cuello AC (1992) Nerve growth factor-induced synaptogenesis and hypertrophy of cortical cholinergic terminals. Proc Natl Acad Sci USA 89(7):2639–2643

    Article  PubMed  CAS  Google Scholar 

  20. Panni MK, Cooper JD, Sofroniew MV (1998) Ganglioside GM1 potentiates NGF action on axotomised medial septal cholinergic neurons. Brain Res 812(1–2):76–80

    Article  PubMed  CAS  Google Scholar 

  21. Di Patre PL, Casamenti F, Cenni A, Pepeu G (1989) Interactions between nerve growth factor and GM1 monosialoganglioside in preventing cortical choline acetyltransferase and high affinity choline uptake decrease after lesion of the nucleus basalis. Brain Res 480(1–2):219–224

    Article  PubMed  Google Scholar 

  22. Cuello AC, Garofalo L, Liberini P, Maysinger D (1994) Cooperative effects of gangliosides on trophic factor-induced neuronal cell recovery and synaptogenesis: studies in rodents and subhuman primates. Prog Brain Res 101:337–355

    Article  PubMed  CAS  Google Scholar 

  23. Rabin SJ, Mocchetti IJ (1995) GM1 ganglioside activates the high-affinity nerve growth factor receptor trkA. J Neurochem 65(1):347–354

    Article  PubMed  CAS  Google Scholar 

  24. Duchemin AM, Ren Q, Mo L, Neff NH, Hadjiconstantinou MJ (2002) GM1 ganglioside induces phosphorylation and activation of Trk and Erk in brain. J Neurochem 81(4):696–707

    Article  PubMed  CAS  Google Scholar 

  25. Farooqui T, Yates AJ (1998) Effect of GM1 on TrkA dimerization. Ann NY Acad Sci 19(845):407

    Article  Google Scholar 

  26. Fahnestock M, Michalski B, Xu B, Coughlin MD (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

    Article  PubMed  CAS  Google Scholar 

  27. Marcinkiewicz M, Seidah NG, Chrétien M (1996) Implications of the subtilisin/kexin-like precursor convertases in the development and function of nervous tissues. Acta Neurobiol Exp (Wars) 56(1):287–298

    CAS  Google Scholar 

  28. Mowla SJ, Pareek S, Farhadi HF, Petrecca K, Fawcett JP, Seidah NG, Morris SJ, Sussing WS, Murphy RA (1999) Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J Neurosci 19(6):2069–2080

    PubMed  CAS  Google Scholar 

  29. Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948

    Article  PubMed  CAS  Google Scholar 

  30. Chao MV, Hempstead BL (1995) P75 and Trk: a two-receptor system. Trends Neurosci 18(7):321–328

    Article  PubMed  CAS  Google Scholar 

  31. Bloch A, Théoden H (1995) Characterization of nerve growth factor (NGF) release from hippocampal neurons: evidence for a constitutive and an unconventional sodium-dependent regulated pathway. Eur J Neurosci 7(6):1220–1228

    Article  Google Scholar 

  32. Bloch A, Théoden H (1996) Localization of cellular storage compartments and sites of constitutive and activity-dependent release of nerve growth factor (NGF) in primary cultures of hippocampal neurons. Mol Cell Neurosci 7(3):173–190

    Article  Google Scholar 

  33. Bruno MA, Cuello AC (2006) Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc Natl Acad Sci USA 103:6735–6740

    Article  PubMed  CAS  Google Scholar 

  34. Grimes ML, Zhou J, Beattie EC, Yuen EC, Hall DE, Valletta JS, Top KS, Laval JH, Bennett NW, Mobley WC (1996) Endocytosis of activated TrkA: evidence that nerve growth factor induces formation of signaling endosomes. J Neurosci 16:7950–7964

    PubMed  CAS  Google Scholar 

  35. Sofroniew MV, Howe CL, Mobley WC (2001) Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 24:1217–1281

    Article  PubMed  CAS  Google Scholar 

  36. Cuello AC (1994) Trophic factor therapy in the adult CNS: remodelling of injured basalo-cortical neurons. Prog Brain Res 100:213–221

    Article  PubMed  CAS  Google Scholar 

  37. Debeir T, Saragovi U, Cuello AC (1999) A nerve growth factor mimetic TrkA antagonist causes withdrawal of cortical cholinergic boutons in the adult rat. PNAS 96(7):4067–4072

    Article  PubMed  CAS  Google Scholar 

  38. Brown RE, Milner PM (2003) The legacy of Donald O. Hebb: more than the Hebb synapse. Nat Rev Neurosci 4(12):1013–1019

    Article  PubMed  CAS  Google Scholar 

  39. 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. Brain Res Mol Brain Res 5(1):1–7

    Article  PubMed  CAS  Google Scholar 

  40. Scott SA, Mufson EJ, Weingartner JA, Skau KA, Crutcher KA (1995) Nerve growth factor in Alzheimer’s disease: increased levels throughout the brain coupled with declines in nucleus basalis. J Neurosci 15(9):6213–6221

    PubMed  CAS  Google Scholar 

  41. Bruno MA, Leon WC, Fragoso G, Mushynski WE, Almazan G, Cuello AC (2009) Amyloid β-induced nerve growth factor dysmetabolism in Alzheimer disease. J Neuropath Exp Neurol 68(8):857–869

    Google Scholar 

  42. Allard S, Leon WC, Pakavathkumar P, Bruno MA, Ribeiro-da-Silva A, Cuello AC (2012) Impact of the NGF maturation and degradation pathway on the cortical cholinergic system phenotype. J Neurosci 32(6):2002–2012

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada

    A. Claudio Cuello

Authors
  1. A. Claudio Cuello
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Claudio Cuello.

Additional information

Special issue: In honor of Bob Leeden.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cuello, A.C. Gangliosides, NGF, Brain Aging and Disease: A Mini-Review with Personal Reflections. Neurochem Res 37, 1256–1260 (2012). https://doi.org/10.1007/s11064-012-0770-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-012-0770-9

Keywords

Search

Navigation