Nerve Growth Factor Expression and Function in the CNS

Abstract

Nerve growth factor (NGF) is a protein that is known to promote the survival, differentiation, and process extension of a number of neuronal systems to various degrees during development and, in some cases, in mature organisms. Deficits in the NGF responsiveness of basal forebrain cholinergic neurons may contribute to pathological changes in the aged central nervous system. One gene whose expression appears to be regulated by NGF is the amyloid protein precursor (APP), which encodes the β/A4 protein component of amyloid deposits in aged and Alzheimer’s diseased brain. In order to understand the regulation of APP gene expression by NGF in vivo, we have initiated studies in the basal forebrain of adult and aged rats using in situ hybridization and quantitative mRNA analysis of different APP transcripts, NGF receptor (NGFr) and choline acetyltransferase (ChAT) mRNAs. NGF or vehicle was infused into aged and young rats. In young adult rats, chronic NGF infusion produces robust increases in APP mRNA hybridization, NGFr mRNA hybridization, NGFr immunoreactivity, ChAT mRNA hybridization, and hypertrophy of ChAT immunoreactivity and mRNApositive neurons. NGF treatment also increases the ratio of APP-695 mRNA to APP-751 mRNA in the basal forebrain. Control aged rats with spatial memory deficits show increased levels of APP-751 mRNA in the forebrain as compared with aged nonimpaired or young control rats. We are currently examining whether NGF treatment in aged animals can effect changes in APP gene expression associated with behavioral impairment.