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Overview of Overview of NGF Signaling

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I. A Nobel Discovery:

The first member of the neurotrophin family, Nerve Growth Factor (NGF), was discovered by Rita Levi-Montalcini in 1953 which led to her receiving the Nobel Prize in 1986.1,2  In her seminal study, Levi-Montalcini grafted a piece of mouse sarcoma tissue onto chick embryos whose wing buds had been removed.3,4  Despite the absence of wing buds, the chicken embryo nearby sensory and sympathetic ganglia grew due to the release of a soluble factor from the adjacent tumor tissue.1,3  Further investigation by biochemist Stanley Cohen, led to isolation of the growth-promoting soluble factor and its official designation as NGF. 


II. NGF Signaling Pathway:

Decades following Levi-Montalcini’s discovery, research established NGF essential for the development of the peripheral nervous system (PNS) and functional integrity within the central nervous system (CNS).4  Within the peripheral nervous system, NGF dynamically controls neurotransmitters and neuropeptides synthesis and phenotypic maintenance of neurons.5  In the central nervous system (CNS), the greatest amount of NGF is produced in the cortex, the hippo-campus and in the pituitary gland.  Basal forebrain cholinergic neurons (BFCNs) rely on NGF for their maintenance and survival within the basal forebrain complex (BFC); thereby, influencing attention, arousal, motivation, memory and consciousness. 1,3,6,7  NGF is also a direct anti-amyloidogenic factor.8,9

NGF biological transduction is carried out by the specific receptor tropomyosin kinase receptor A (TrkA) and/or the p75 Neutrophin Receptor (p75NTR).10  Once activated by NGF, TrkA promotes downstream signaling via Ras-mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), and Phospholipase C (PLC) –γ which regulate various cellular functions and fates.11,12  In the absence of TrkA, NGF stimulates cellular apoptosis by binding to p75NTR at a lower and non-selective affinity and transduces through Jun kinase, NF-kB, and ceramine production.10,13,14


III. NGF Pathophysiology and Therapeutic Capability:

The cholinergic neurons profoundly degenerate in Alzheimer’s disease (AD) and contribute to cognitive decline.15,16 Therefore, NGF is indicated as a potential preventative and/or therapeutic factor for neurodegenerative disorders.  NGF as a therapeutic candidate extends beyond its BFCN regulation.  Restoring proNGF/NGF homeostasis represents a strategy to combat early neurodegeneration and to provide neuroprotection in neurodegenerative conditions through anti-amyloidogenic action and management within astrocyte and microglia cells.17,18 

Within neurodegenerative disorders, the greatest challenge in the systemic delivery of NGF resides in its inability to cross the blood–brain barrier (BBB).19  The second limit delineates NGF intrinsic property of being one of the key molecules for mediating inflammatory pain and neuropathic pain in the PNS; thereby, increasing pain sensitivity.20–22  A potential approach to overcome such limitations is represented by gene therapy which increase the expression of NGF.4  The olfactory pathway is a promising, non-invasive route for drug delivery to the brain, which has potential for the treatment of neurodegenerative diseases.23,24  Finally, another investigated route to deliver NGF to the brain in a safe and effective manner is the topical administration of NGF on ocular surface.25



Below is the current list of Bethyl antibodies involved in cell division:



1. Levi-Montalcini R. The nerve growth factor 35 years later. Science (New York, N.Y.). 1987;237(4819):1154–1162.

2. Ebendal T. Function and evolution in the NGF family and its receptors. Journal of Neuroscience Research. 1992;32(4):461–470. doi:10.1002/jnr.490320402

3. Levi-Montalcini R. Effects of mouse tumor transplantation on the nervous system. Annals of the New York Academy of Sciences. 1952;55(2):330–344.

4. Aloe L, Rocco M, Bianchi P, Manni L. Nerve growth factor: from the early discoveries to the potential clinical use. Journal of Translational Medicine. 2012;10(1):239. doi:10.1186/1479-5876-10-239

5. Otten U, Schwab M, Gagnon C, Thoenen H. Selective induction of tyrosine hydroxylase and dopamine beta-hydroxylase by nerve growth factor: comparison between adrenal medulla and sympathetic ganglia of adult and newborn rats. Brain Research. 1977;133(2):291–303.

6. Hefti F, Knusel B, Lapchak PA. Protective effects of nerve growth factor and brain-derived neurotrophic factor on basal forebrain cholinergic neurons in adult rats with partial fimbrial transections. Progress in Brain Research. 1993;98:257–263.

7. Mufson EJ, Kroin JS, Sendera TJ, Sobreviela T. Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Progress in Neurobiology. 1999;57(4):451–484.

8. Rossner S, Ueberham U, Schliebs R, Perez-Polo JR, Bigl V. p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells. Journal of Neurochemistry. 1998;71(2):757–766.

9. Tian L, Guo R, Yue X, Lv Q, Ye X, Wang Z, Chen Z, Wu B, Xu G, Liu X. Intranasal administration of nerve growth factor ameliorate β-amyloid deposition after traumatic brain injury in rats. Brain Research. 2012;1440:47–55. doi:10.1016/j.brainres.2011.12.059

10. Friedman WJ, Greene LA. Neurotrophin signaling via Trks and p75. Experimental Cell Research. 1999;253(1):131–142. doi:10.1006/excr.1999.4705

11. Klesse LJ, Parada LF. Trks: signal transduction and intracellular pathways. Microscopy Research and Technique. 1999;45(4–5):210–216. doi:10.1002/(SICI)1097-0029(19990515/01)45:4/5<210::AID-JEMT4>3.0.CO;2-F

12. Reichardt LF. Neurotrophin-regulated signalling pathways. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2006;361(1473):1545–1564. doi:10.1098/rstb.2006.1894

13. Schor NF. The p75 neurotrophin receptor in human development and disease. Progress in Neurobiology. 2005;77(3):201–214. doi:10.1016/j.pneurobio.2005.10.006

14. Miller FD, Kaplan DR. Neurotrophin signalling pathways regulating neuronal apoptosis. Cellular and molecular life sciences: CMLS. 2001;58(8):1045–1053. doi:10.1007/PL00000919

15. Conner JM, Culberson A, Packowski C, Chiba AA, Tuszynski MH. Lesions of the Basal forebrain cholinergic system impair task acquisition and abolish cortical plasticity associated with motor skill learning. Neuron. 2003;38(5):819–829.

16. Bartus RT, Dean RL, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science (New York, N.Y.). 1982;217(4558):408–414.

17. Capsoni S, Brandi R, Arisi I, D’Onofrio M, Cattaneo A. A dual mechanism linking NGF/proNGF imbalance and early inflammation to Alzheimer’s disease neurodegeneration in the AD11 anti-NGF mouse model. CNS & neurological disorders drug targets. 2011;10(5):635–647.

18. Cattaneo A, Calissano P. Nerve growth factor and Alzheimer’s disease: new facts for an old hypothesis. Molecular Neurobiology. 2012;46(3):588–604. doi:10.1007/s12035-012-8310-9

19. Poduslo JF, Curran GL. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Research. Molecular Brain Research. 1996;36(2):280–286.

20. Lewin GR, Ritter AM, Mendell LM. Nerve growth factor-induced hyperalgesia in the neonatal and adult rat. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 1993;13(5):2136–2148.

21. Watanabe T, Ito T, Inoue G, Ohtori S, Kitajo K, Doya H, Takahashi K, Yamashita T. The p75 receptor is associated with inflammatory thermal hypersensitivity. Journal of Neuroscience Research. 2008;86(16):3566–3574. doi:10.1002/jnr.21808

22. Anand P, Terenghi G, Warner G, Kopelman P, Williams-Chestnut RE, Sinicropi DV. The role of endogenous nerve growth factor in human diabetic neuropathy. Nature Medicine. 1996;2(6):703–707.

23. Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T. Effect of intranasal insulin on cognitive function: a systematic review. The Journal of Clinical Endocrinology and Metabolism. 2012;97(2):366–376. doi:10.1210/jc.2011-1802

24. Guastella AJ, Graustella AJ, MacLeod C. A critical review of the influence of oxytocin nasal spray on social cognition in humans: evidence and future directions. Hormones and Behavior. 2012;61(3):410–418. doi:10.1016/j.yhbeh.2012.01.002

25. Lambiase A, Pagani L, Di Fausto V, Sposato V, Coassin M, Bonini S, Aloe L. Nerve growth factor eye drop administrated on the ocular surface of rodents affects the nucleus basalis and septum: biochemical and structural evidence. Brain Research. 2007;1127(1):45–51. doi:10.1016/j.brainres.2006.09.102