title: Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease.
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 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.
authors.affiliation: Department of Biochemistry, Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland. colm.cunningham@tcd.ie
authors.forename: Colm
authors.initials: C
authors.lastname: Cunningham
authors.forename: Suzanne
authors.initials: S
authors.lastname: Campion
authors.forename: Katie
authors.initials: K
authors.lastname: Lunnon
authors.forename: Carol L
authors.initials: CL
authors.lastname: Murray
authors.forename: Jack F C
authors.initials: JF
authors.lastname: Woods
authors.forename: Robert M J
authors.initials: RM
authors.lastname: Deacon
authors.forename: J Nicholas P
authors.initials: JN
authors.lastname: Rawlins
authors.forename: V Hugh
authors.initials: VH
authors.lastname: Perry
mesh_terms: 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
chemical_list: D008070:Lipopolysaccharides
references.citation: Physiol Behav. 2005 Jun 30;85(3):278-88
references.pmid: 15936787
references.citation: Alzheimer Dis Assoc Disord. 1997 Mar;11(1):16-20
references.pmid: 9071440
references.citation: J Neurosci. 2005 Sep 28;25(39):8843-53
references.pmid: 16192374
references.citation: J Neurosci. 2005 Oct 5;25(40):9275-84
references.pmid: 16207887
references.citation: Neurobiol Dis. 2005 Nov;20(2):283-95
references.pmid: 15886005
references.citation: Ann Neurol. 2006 Feb;59(2):219-28
references.pmid: 16402383
references.citation: Neurobiol Aging. 2006 May;27(5):717-22
references.pmid: 15890435
references.citation: Neurobiol Aging. 2006 May;27(5):723-32
references.pmid: 15893410
references.citation: Neurobiol Aging. 2007 May;28(5):639-47
references.pmid: 16697488
references.citation: Nat Protoc. 2006;1(1):118-21
references.pmid: 17406222
references.citation: Age Ageing. 1997 Nov;26(6):423-7
references.pmid: 9466291
references.citation: Behav Brain Res. 2005 Apr 15;159(1):145-51
references.pmid: 15795008
references.citation: J Virol. 2005 Apr;79(8):5174-84
references.pmid: 15795301
references.citation: Brain Behav Immun. 2007 May;21(4):490-502
references.pmid: 17321719
references.citation: Brain Behav Immun. 2007 Aug;21(6):836-50
references.pmid: 17367989
references.citation: Physiol Behav. 2007 Aug 15;91(5):561-5
references.pmid: 17499821
references.citation: Brain Behav Immun. 2008 Mar;22(3):301-11
references.pmid: 17951027
references.citation: Behav Brain Res. 2008 May 16;189(1):126-38
references.pmid: 18261809
references.citation: Brain. 2008 Jul;131(Pt 7):1880-94
references.pmid: 18504291
references.citation: Arch Int Pharmacodyn Ther. 1964 Dec 1;152:277-84
references.pmid: 14265648
references.citation: Dement Geriatr Cogn Disord. 2005;19(2-3):158-63
references.pmid: 15627764
references.citation: J Neurosci. 2005 Feb 16;25(7):1788-96
references.pmid: 15716415
references.citation: Age Ageing. 1999 Oct;28(6):551-6
references.pmid: 10604507
references.citation: Neurobiol Aging. 2000 May-Jun;21(3):383-421
references.pmid: 10858586
references.citation: CMAJ. 2000 Oct 17;163(8):977-81
references.pmid: 11068569
references.citation: J Neuropathol Exp Neurol. 2001 Feb;60(2):173-82
references.pmid: 11273005
references.citation: Int Psychogeriatr. 2000 Dec;12(4):473-81
references.pmid: 11263714
references.citation: Eur J Neurosci. 2001 Jul;14(2):401-9
references.pmid: 11553290
references.citation: Brain Res Bull. 2001 Dec;56(6):581-8
references.pmid: 11786245
references.citation: Neuropathol Appl Neurobiol. 2002 Apr;28(2):107-19
references.pmid: 11972797
references.citation: Neuroscience. 2002;112(1):7-11
references.pmid: 12044467
references.citation: Behav Brain Res. 2002 Jun 15;133(1):57-68
references.pmid: 12048174
references.citation: Behav Neurosci. 2002 Jun;116(3):472-8
references.pmid: 12049328
references.citation: Nat Neurosci. 2002 Sep;5(9):868-73
references.pmid: 12195431
references.citation: BMJ. 2002 Sep 21;325(7365):644-7
references.pmid: 12242179
references.citation: J Am Geriatr Soc. 2002 Oct;50(10):1723-32
references.pmid: 12366629
references.citation: Nat Rev Neurosci. 2003 Feb;4(2):103-12
references.pmid: 12563281
references.citation: J Neurol Neurosurg Psychiatry. 2003 Jun;74(6):788-9
references.pmid: 12754353
references.citation: Eur J Neurosci. 2003 May;17(10):2147-55
references.pmid: 12786981
references.citation: Lancet Neurol. 2002 Sep;1(5):279-84
references.pmid: 12849425
references.citation: BMJ. 2003 Jul 19;327(7407):128
references.pmid: 12869452
references.citation: J Neurosci. 2004 Feb 11;24(6):1340-9
references.pmid: 14960605
references.citation: Neuropsychol Rev. 2004 Jun;14(2):87-98
references.pmid: 15264710
references.citation: Toxicology. 2004 Sep 1;201(1-3):197-207
references.pmid: 15297033
references.citation: Eur J Pharmacol. 2004 Oct 1;500(1-3):399-411
references.pmid: 15464048
references.citation: Infect Immun. 1978 Feb;19(2):357-68
references.pmid: 631875
references.citation: Glia. 1993 Jan;7(1):60-7
references.pmid: 8423063
references.citation: Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6155-9
references.pmid: 8327496
references.citation: J Gerontol. 1993 Sep;48(5):M181-6
references.pmid: 8366260
references.citation: Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3032-5
references.pmid: 7708769
references.citation: Neuroscience. 1996 Sep;74(1):1-5
references.pmid: 8843071
references.citation: Physiol Behav. 2005 Sep 15;86(1-2):244-51
references.pmid: 16115658