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

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

Alzheimer's disease, cytokines, delirium, inflammation, microglial priming, neurodegeneration, systemic
0006-3223
304-312
Cunningham, Colm
3bc1d897-f0f5-4112-abf4-1a10c2e92a6b
Campion, Suzanne
3d67e320-84c4-4cd3-b278-09b0c8a4c040
Lunnon, Katie
108767cd-0119-49ee-b22c-7c20f8a86eb3
Murray, Carol L
a525fccc-c559-4887-9969-67298c68405b
Woods, Jack F. C.
c49b3324-1e2e-492c-896b-f98dfe3f2975
Deacon, Robert M.J.
5e6a7058-2bbf-45f3-8c55-09a7f4a1dc9f
Rawlins, Nicholas P
44afdce0-de91-42d3-a191-3d5fbd556904
Perry, V.Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Cunningham, Colm
3bc1d897-f0f5-4112-abf4-1a10c2e92a6b
Campion, Suzanne
3d67e320-84c4-4cd3-b278-09b0c8a4c040
Lunnon, Katie
108767cd-0119-49ee-b22c-7c20f8a86eb3
Murray, Carol L
a525fccc-c559-4887-9969-67298c68405b
Woods, Jack F. C.
c49b3324-1e2e-492c-896b-f98dfe3f2975
Deacon, Robert M.J.
5e6a7058-2bbf-45f3-8c55-09a7f4a1dc9f
Rawlins, Nicholas P
44afdce0-de91-42d3-a191-3d5fbd556904
Perry, V.Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4

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).

Record type: Article

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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More information

Published date: 15 February 2009
Keywords: Alzheimer's disease, cytokines, delirium, inflammation, microglial priming, neurodegeneration, systemic
Organisations: Biological Sciences

Identifiers

Local EPrints ID: 67548
URI: http://eprints.soton.ac.uk/id/eprint/67548
ISSN: 0006-3223
PURE UUID: 60920c36-6447-404e-91ca-e877fb72e5e1

Catalogue record

Date deposited: 24 Aug 2009
Last modified: 13 Mar 2024 18:53

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Contributors

Author: Colm Cunningham
Author: Suzanne Campion
Author: Katie Lunnon
Author: Carol L Murray
Author: Jack F. C. Woods
Author: Robert M.J. Deacon
Author: Nicholas P Rawlins
Author: V.Hugh Perry

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