Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease.
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 microg/kg), at 12 weeks postinoculation (PI), resulted in heightened CNS interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-beta (IFN-beta) transcription and microglial IL-1beta 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 microg/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.
Cunningham
Colm
C
Department of Biochemistry, Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland. colm.cunningham@tcd.ie
Campion
Suzanne
S
Lunnon
Katie
K
Murray
Carol L
CL
Woods
Jack F C
JF
Deacon
Robert M J
RM
Rawlins
J Nicholas P
JN
Perry
V Hugh
VH
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001831:Body Temperature / Q000187:drug effects; D003071:Cognition / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications* / Q000523:psychology*; D007263:Infusions, Parenteral; D008070:Lipopolysaccharides / Q000494:pharmacology; D008137:Longitudinal Studies; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000523:psychology*; D011597:Psychomotor Performance / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008070:Lipopolysaccharides
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