NGF-mediated alteration of NF-κB binding activity after partial immunolesions to rat cholinergic basal forebrain neurons

Abstract

There are age-associated cognitive and cholinergic deficits in the neurotrophin-dependent cholinergic basal forebrain neurons (CBFNs). There are also increases in the activity of the transcription factor NF-κB in the aged rodent brain that may reflect chronic enhancement of stress response signaling. We used partial immunolesions (PIL) to CBFN to examine the role of endogenous NGF on choline acetyltransferase (ChAT) activity and NGF-mediated NF-κB alteration after cholinergic deafferentation. We injected 192 IgG-saporin, an immunotoxin selectively taken up by neurotrophin receptor p75NTR-bearing neurons, into lateral ventricles, followed by infusions of anti-NGF to assess NF-κB, ChAT and NGF responses to PIL after anti-NGF infusion. Treatment with anti-NGF decreased ChAT activity by 17–34% in the cortex, hippocampus, and olfactory bulb and PIL decreased ChAT activity by 47–73%. Changes in AChE activity levels paralleled those observed for ChAT after PIL. NGF protein levels in the olfactory bulb, but not the cortex or hippocampus, increased significantly after PIL treatment. Infusion of anti-NGF abolished the PIL-induced eight-fold NGF increase in CNS. NF-κB binding activity to the IgG-κB and ChAT specific NF-κB consensus sequences, increased in the cortex but not hippocampus after PIL followed by anti-NGF infusion. It is likely that immunolesion-induced changes in ambient NGF levels may perturb NF-κB activity.