Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease.
Peripheral infections in mammals are characterised by local, systemic and CNS effects. The latter give rise to sickness behaviour. Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) are thought to be important mediators of this neuro-immune signalling (Cartmell et al., 1999). There is anecdotal evidence suggesting that peripheral infections in patients with Alzheimer's disease have more severe behavioural consequences than those in otherwise healthy elderly subjects, and it is well known that brain microglia are activated in the elderly and in Alzheimer's disease (McGeer et al., 1987). Using ME7-induced murine prion disease as a model of chronic neurodegeneration that displays chronic microglial activation, and the intra-peritoneal injection of bacterial lipopolysaccharide to mimic a peripheral infection, we have shown that the temperature and activity responses of animals with pre-clinical prion disease were exaggerated compared with controls, and that this was associated with a significant increase in brain levels of IL-1beta. We hypothesise that prior priming of microglia by the degenerative process, followed by further activation through signalling from the periphery, resulted in increased brain IL-1beta synthesis and the consequent acute sickness behavioural responses. These findings demonstrate an interaction between peripheral infection and pre-existing CNS inflammation and suggest that further stimulation of an already primed microglial population by a peripheral infection may drive disease progression in chronic inflammatory conditions such as Alzheimer's disease and prion disease.
Combrinck
M I
MI
University Department of Pharmacology, Oxford, UK.
Perry
V H
VH
Cunningham
C
C
D000818:Animals; D001424:Bacterial Infections / Q000150:complications*; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D017096:Prion Diseases / Q000503:physiopathology / Q000523:psychology*; D012803:Sick Role
D007375:Interleukin-1; D008070:Lipopolysaccharides