In brain, activation of glial cells induces nitric oxide synthase (NOS2) expression, which can contribute to damage in disease and trauma, including ischemia, multiple sclerosis, and Alzheimer's disease (AD). Prevention of NOS2 expression could reduce inflammatory damage. The signaling pathways underlying NOS2 expression are not fully characterized, however it is clear that transcription factor NFkB is crucial. We characterized NOS2 expression in rat astrocytes, and now will characterize signals leading to NOS2 expression in human astrocytes and rat and human microglia. Recent studies of NFkB regulation by inhibitory IkB proteins show that NOS2 induction requires persistent, not transient activation NFkB activation. Experiments will test the hypothesis that astroglial and microglial NOS2 expression also requires persistent NFkB activation. Since expression of a stimulatory form of IkB-beta is associated with persistent NFkB activation, we willdetermine if LPS or cytokines induce re-expression of this isoform. We showed two mechanisms toreduce NOS2, incubation with Norepinephrine (NE) or induction of a heat shock response (HSR),whether these methods prevent human glial NOS2 is not known. We propose that mechanisms which these two suppressors both cause an increase inhibitory IkB proteins, which we will test, and if so if those proteins enter the nucleus to inhibit NFkB. Our results suggest that depletion of brain NE levels increases brain inflammation, which is relevant to AD where noradrenergic neurons are lost.We will test this in vivo by chemical lesioning of noradrenergic neurons, and by using knockout mice which lack NE. The responses to injections of amyloid beta into the cortex, and whether the HSR reverses those responses, will be determined. These experiments will provide targets for therapeutic intervention to reduce pathological NOS2 in brain, and help develop a new animal model for examining brain inflammatory in the context of diminished NE levels.
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