In experimental as well as in natural scrapie, transmissible spongiform encephalopathies (TSEs), the infectious agent, closely related to PrPsc, an abnormal isoform of the cellular prion protein, invades and replicates in lymphoid organs such as spleen before affecting the brain. To clarify the cellular requirements for the possible neuroinvasion of scrapie agent from the spleen to the central nervous system, we have studied the sympathetic innervation within the lymphoid territories of the spleen. These noradrenergic fibers originating from the coeliomesenteric ganglia were examined with regard to PrPsc-associated cells in spleen of adult sheep severely affected with natural scrapie. Using a double immunolabelling strategy, we demonstrated the proximity of noradrenergic endings with PrPsc-accumulating cells, strengthening its possible implication in the neuroinvasion process.