NGF in CNS: Sites of Synthesis and Effects of Novel Ways to Administer NGF on Intrinsic Cholinergic Neurons and Grafts of Cholinergic Neurons and Their Target Areas

Abstract

Recent evidence suggests that nerve growth factor (NGF) is present in the central nervous system and that cholinergic neurons are among those that respond to, and may depend on, NGF. We have recently been able to locate NGF mRNA to pyramidal and granular cells of the hippocampal formation and have proposed a neuron-to-neuron interaction between such NGF-producing cells and the cholinergic projections to the hippocampal formation. When fetal basal forebrain tissue rich in cholinergic neuroblasts is grafted to the anterior chamber of the eye, the grafts will reach a larger final volume and contain a larger number of both cholinergic and noncholinergic neurons if supported by repeated NGF injections into the eye chamber. Conversely, grafts of cerebral cortex and hippocampus will both stop growing earlier in the presence of exogenous NGF, suggesting that NGF inhibits cell division and initiates differentiation in these cholinergic target areas. Cholinergic cell-rich cell suspensions were also injected into the cerebral cortex of animals with ibotenic acid-induced lesions of nucleus basalis. Again, NGF, infused chronically using a dialysis fiber-osmotic minipump assembly, enhanced graft survival and cholinergic reinnervation of host cortex. A genetically engineered cell line that produces and secretes recombinant NGF has been tried as an alternative continuous source of NGF. When compared with the parent cell line, the NGF-oversecreting cells were found able to evoke cholinergic growth responses in intact cholinergic intrinsic neurons in both cortex and striatum, to rescue cholinergic neurons in the basal forebrain after fimbria-fornix lesions, and to stimulate grafts of fetal cholinergic neurons in the brain. Genetically engineered cells thus open up new possibilities for future treatment strategies in neurodegenerative diseases, such as Alzheimer’s disease, in which treatment with neurotrophic factors might prove beneficial.