Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease

Cunningham, Colm, Campion, Suzanne, Lunnon, Katie, Murray, Carol L, Woods, Jack F. C., Deacon, Robert M.J., Rawlins, Nicholas P and Perry, V.Hugh (2009) Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biological Psychiatry, 65 (4), 304-312. (doi:10.1016/j.biopsych.2008.07.024).

Abstract

Background

Chronic neurodegeneration results in microglial activation, but the contribution of inflammation to the progress of neurodegeneration remains unclear. We have shown that microglia express low levels of proinflammatory cytokines during chronic neurodegeneration but are “primed” to produce a more proinflammatory profile after systemic challenge with bacterial endotoxin (lipopolysaccharide [LPS]).
Methods

Here, we investigated whether intraperitoneal (IP) challenge with LPS, to mimic systemic infection, in the early stages of prion disease can 1) produce exaggerated acute behavioral (n = 9) and central nervous system (CNS) inflammatory (n = 4) responses in diseased animals compared with control animals, and 2) whether a single LPS challenge can accelerate disease progression (n = 34–35).
Results

Injection of LPS (100 ?g/kg), at 12 weeks postinoculation (PI), resulted in heightened CNS interleukin-1 beta (IL-1?), tumor necrosis factor-alpha (TNF-?), and interferon-beta (IFN-?) transcription and microglial IL-1? translation in prion-diseased animals relative to control animals. This inflammation caused exaggerated impairments in burrowing and locomotor activity, and induced hypothermia and cognitive changes in prion-diseased animals that were absent in LPS-treated control animals. At 15 weeks PI, LPS (500 ?g/kg) acutely impaired motor coordination and muscle strength in prion-diseased but not in control animals. After recovery, these animals also showed earlier onset of disease-associated impairments on these parameters.
Conclusions

These data demonstrate that transient systemic inflammation superimposed on neurodegenerative disease acutely exacerbates cognitive and motor symptoms of disease and accelerates disease progression. These deleterious effects of systemic inflammation have implications for the treatment of chronic neurodegeneration and associated delirium.

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