A fundamental issue in current biology is the question of maintaining a critical balance between cell survival and cell death, both during development and in adulthood. In the nervous system, a family of neurotrophins which includes nerve growth factor (NGF), BDNF, and neurotrophins 3/4/5, maintains this critical balance. The best characterized of these is NGF, a neurotrophic protein which is important for the growth and survival of diverse peripheral and central neurons. It is expressed within discrete CNS areas and is secreted by tissues targeted by sympathetic and some sensory neurons. The effects of NGF on neuronal growth and survival are mediated by a high affinity cell surface receptor TrkA and a low affinity receptor p75(NTR).Activation of TrkA by NGF is followed by receptor dimerization and trans-autophosphorylation of tyrosine residues on TrkA, which then act as docking sites for a variety of downstream signaling effectors and adaptor proteins. Adaptor proteins such as SOS and GRB2 are recruited to TrkA leading to activation of the Ras-Raf-MEK-ERK, PI3K-AKT signaling pathways. PLC-γ phosphorylation results in the activation of the PKC signaling pathway. The Rac-RhoA-ROCK pathway results in actin polymerization and neurite outgrowth and differentiation, while AKT signaling regulates neuronal survival.
NGF binds with lower affinity to p75(NTR), which has no tyrosine kinase domain. The main physiological function of p75(NTR) is to activate TrkA-independent signal transduction cascades involving sphingomyelinase, NF-κB and JNK. p75(NTR) activates a survival pathway that may involve the activation of NF-κB through TRAF-6, whereas limiting amounts of p75(NTR) may activate the JNK death signaling pathway. p75(NTR) can also activate sphingomyelinase to produce ceramide. Ceramide is a key player in the induction of neuronal apoptosis.
NGF is the most potent growth factor for cholinergic neurons and it influences the proliferation, differentiation, survival and death of neurons. It is essential for the health and well-being of the nervous system. Alterations in NGF levels have been implicated in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, as well as psychiatric disorders such as depression and substance abuse. It is a promising candidate for treating Alzheimer's disease.