Overexpression of tumour necrosis factor ? in the brain of transgenic mice differentially alters nerve growth factor levels and choline acetyltransferase activity

Tumour necrosis factor ? (TNF-?) is a pleiotrophic cytokine synthesized primarily by macrophages and monocytes, which exerts a variety of biological activities during inflammatory responses, immune reactions, and wound healing. Within the central nervous system (CNS), the basal levels of TNF-? are almost undetectable, but increase after neurological insults. Using transgenic mice expressing high levels of TNF-? in the CNS we investigated the effect of this cytokine on the levels of brain nerve growth factor (NGF), a neurotrophin playing a crucial role in the development, maintenance and regeneration of basal forebrain cholinergic neurons. The immunoenzymatic assay and in situ hybridization revealed that the constitutive expression of NGF decreased in the hippocampus, increased in the hypothalamus, while remained unchanged in the cortex. Moreover, septal cholinergic neurons which receive trophic support from NGF produced in the hippocampus display loss of choline acetyltransferase immunoreactivity, suggesting that the reduced availability of NGF may influence negatively the synthesis of brain cholinergic neurons. These observations indicate that the basal level of brain NGF can be influenced negatively or positively by local expression of TNF-? and that this cytokine, through dose-dependent regulation of NGF synthesis and release, may be involved in neurodegenerative events associated with aging.