Responses of young and aged rat CNS to partial cholinergic immunolesions and NGF treatment.

The cholinergic neurons of the basal forebrain (CNBF) are the major source of cholinergic innervation of the cortex and hippocampus. In Alzheimer's disease and aged brain, there are severe losses of cholinergic neurons in the nucleus basalis of Meynert, leading to a reduction of cortical cholinergic activity which correlates with the severity of cognitive deficits. While there is evidence that aged central nervous system (CNS) displays impaired stress response signaling, pharmacologic treatments with neurotrophic factors appear to ameliorate these age-associated cholinergic deficits. To mimic these cholinergic deficits in experimental animals and study the acute effects of nerve growth factor (NGF), we induced a partial lesion of CBFNs by the intracerebroventricular (i.c.v.) injection of the cholinergic immunotoxin 192IgG-saporin, in groups of 3- and 30-month-old rats. The lesion was followed 14 days later by i.c.v. administration of NGF, known to restore partial immunolesion-induced cholinergic deficits in rat CNS, and all rats were killed 2 days after the NGF treatment. Here we report the effects of partial immunolesions on the levels of choline acetyltransferase (ChAT) activity and NGF receptor mRNA levels in the basal forebrain of 3- and 30-month-old rats. Because of their presence in the promoters of the NGF, NGF receptors, and ChAT genes, we also measured DNA-binding activity of the transcription factors NFB and AP-1 in the cortex and hippocampus. We discuss these findings in the context of endogenous NGF-mediated signal transduction mechanisms and conclude that we have evidence for age-associated decreases in endogenous NGF responses to partial deafferentation of the basal forebrain cholinergic projections.