Beta-Amyloid-Dependent Expression of NOS2in Neurons: Prevention by an α2-Adrenergic Antagonist

Abstract

The neurotransmitter noradrenaline (NA) exerts important antiinflammatory effects on glial cells including suppression of the inducible form of nitric oxide synthase (NOS2). The authors examined the consequences of manipulating NA in vivo by treating adult rats with the neurotoxin DSP4, which selectively lesions noradrenergic neurons of the locus ceruleus (LC), and reduces cortical NA levels. Following LC lesion, intracortical injection of aggregated amyloid beta 1–42 (Aβ1–42) caused appearance of NOS2 within neurons, and increased neuronal damage assessed by staining for nonphosphorylated neurofilament proteins with antibody SMI-32. Co-treatment with a selective α2-adrenergic antagonist reduced neuronal NOS2 staining as well as SMI-32 staining. Neuronal damage was dependent on NOS2 expression since injection of Aβ1–42 into DSP4-treated NOS2-deficient mice did not result in neuronal damage. These results demonstrate that decrease of NA levelsin vivo can exacerbate inflammatory responses and neuronal damage due to inflammatory stimuli such as Aβ. These findings suggest that α2-adrenergic antagonists could provide therapeutic benefit in neurological diseases such as AD or PD where LC loss is known to occur.