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

Tumour necrosis factor at (TNF-alpha) is a pleiotrophic cytokine synthesize d primarily by macrophages and monocytes, which exerts a variety of biologi cal activities during inflammatory responses, immune reactions, and wound h ealing. Within the central nervous system (CNS), the basal levels of TNF-al pha are almost undetectable, but increase after neurological insults. Using transgenic mice expressing high levels of TNF-alpha in the CNS, we investi gated the effect of this cytokine on the levels of brain nerve growth facto r (NGF), a neurotrophin playing a crucial role in the development, maintena nce and regeneration of basal forebrain cholinergic neurons. The immunoenzy matic assay and in situ hybridization revealed that the constitutive expres sion of NGF decreased in the hippocampus, increased in the hypothalamus, wh ile 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 red uced availability of NGF may influence negatively the synthesis of brain ch olinergic neurons. These observations indicate that the basal level of brai n NGF can be influenced negatively or positively by local expression of TNF -alpha and that this cytokine, through dose-dependent regulation of NGF syn thesis and release, may be involved in neurodegenerative events associated with aging. (C) 1999 Academic Press.