SYSTEMIC INTERLEUKIN-1-BETA DECREASES BRAIN-DERIVED NEUROTROPHIC FACTOR MESSENGER-RNA EXPRESSION IN THE RAT HIPPOCAMPAL-FORMATION

Brain-derived neurotrophic factor is selectively expressed at relatively high levels in the rat hippocampal formation (for review, see Ref. 12; see also Refs 8, 13, 19, 20, 27) where it is thought to be involved in mechanisms of neurodegeneration and/or neural protection related to the plasticity of hippocampal neurons.12,25 Functional responses to brain-derived neurotrophic factor appear to be mediated by a tyrosine receptor kinase B with the possible involvement of the p75 low-affinity nerve growth factor receptor protein .4,10,11,16,22,23 Among the many characteristics of Alzheimer's disease is an upregulation of immune mediators in and around senile plaques in Alzheimer's disease.7,15,21 Recently, interleukin-1 has been shown to be detrimental to the long-term survival of embryonic hippocampal neurons in culture .2 Thus, if the same occurs in vivo, it is possible that the accumulation of interleukin-1 in Alzheimer's disease hippocampus may be responsible for altered hippocampal neuron synaptic plasticity. This may occur either by a direct action of interleukin-1 on hippocampal neurons or possibly indirectly by stimulating beta-amyloid production.1,7 Other indirect mechanisms may involve growth or survival factors such as the neurotrophin brain-derived neurotrophic factor which is thought to play an important role in the plastic responses of hippocampal neurons.'' A recent study20 showed that brain-derived neurotrophic factor mRNA is selectively decreased in the dentate gyrus in Alzheimer's disease. The reason(s) for the decrease of brain-derived neurotrophic factor mRNA is not known, but one possibility may be associated with the enhanced expression of interleukin-1 in the hippocampus of Alzheimer's disease patients. Therefore, in the present study we determined whether activation of the immune system with lipopolysaccharide, which elevates interleukin-1(24,26) or direct administration of interleukin-1beta affects the prevalence of brain-derived neurotrophic factor or tyrosine receptor kinase B mRNA in the rat brain. We provide novel evidence for the downregulation of brain-derived neurotrophic factor mRNA expression in the rat hippocampal formation following systemic lipopolysaccharide or interleukin-1beta administration.